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    Clinical Trial Results:
    A Phase 3 Open-label Safety Study of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen in HIV-1 Positive Patients with Mild to Moderate Renal Impairment

    Summary
    EudraCT number
    		 2013-000516-25
    Trial protocol
    		 AT   GB   DE   IT   BE   NL   ES  
    Global end of trial date
    18 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2019
    First version publication date
    14 Jul 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-292-0112
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01818596
    WHO universal trial number (UTN)
    		 U1111-1141-7246
    Other trial identifiers
    		 German Clinical Trials Register: DRKS00006487
    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
    18 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) tablet on renal parameters at Week 24 in antiretroviral treatment (ART)-naive and ART-experienced HIV-positive, adults with mild to moderate renal impairment.
    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
    27 Mar 2013
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United States: 174
    Country: Number of subjects enrolled
    Thailand: 31
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Dominican Republic: 6
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    252
    EEA total number of subjects
    26
    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)
    188
    From 65 to 84 years
    64
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Australia, Asia, and Europe. The first participant was screened on 27 March 2013. The last study visit occurred on 18 July 2018.

    Pre-assignment
    Screening details
    		 380 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (Treatment-experienced)
    Arm description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 240 weeks in ART-experienced participants
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
    Investigational medicinal product code
    Other name
    E/C/F/TAF; Genvoya®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150/150/200/10 mg FDC tablet administered once daily with food

    Arm title
    		 Cohort 2 (Treatment-naive)
    Arm description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 188 weeks in ART-naive participants
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
    Investigational medicinal product code
    Other name
    E/C/F/TAF; Genvoya®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150/150/200/10 mg FDC tablet administered once daily with food

    Number of subjects in period 1 [1]
    		Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Started
    242
    6
    Completed
    215
    6
    Not completed
    27
    0
         Withdrew Consent
    5
    -
         Adverse Event
    7
    -
         Death
    3
    -
         Investigator's Discretion
    4
    -
         Protocol Violation
    1
    -
         Lost to follow-up
    7
    -
    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: 4 participants who were enrolled but not treated are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (Treatment-experienced)
    Reporting group description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 240 weeks in ART-experienced participants

    Reporting group title
    Cohort 2 (Treatment-naive)
    Reporting group description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 188 weeks in ART-naive participants

    Reporting group values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive) Total
    Number of subjects
    		 242 6 248
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58 ( 9.9 ) 55 ( 7.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 50 0 50
        Male
    		 192 6 198
    Race
    Units: Subjects
        Asian
    		 34 1 35
        American Indian or Alaska Native
    		 1 0 1
        Black or African American
    		 44 3 47
        Native Hawaiian or Pacific Islander
    		 2 0 2
        White
    		 152 2 154
        Other
    		 7 0 7
        Not Permitted
    		 2 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 31 1 32
        Not Hispanic or Latino
    		 209 5 214
        Not Permitted
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (Treatment-experienced)
    Reporting group description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 240 weeks in ART-experienced participants

    Reporting group title
    Cohort 2 (Treatment-naive)
    Reporting group description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 188 weeks in ART-naive participants

    Subject analysis set title
    Substudy Participants
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 240 weeks

    Primary: Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24

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    End point title
    		 Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 [1]
    End point description
    eGFR is a measurement of the kidney's ability to filter blood. Participants in the Safety Analysis Set (enrolled and received at least 1 dose of study drug) with available data at the respective time point were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Baseline (N = 242, 6)
    55.6 (45.7 to 62.4)
    60.2 (45.0 to 63.2)
        Change at Week 24 (N = 233, 6)
    -0.4 (-4.7 to 4.5)
    -0.3 (-3.6 to 1.3)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24

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    End point title
    		 Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 [2]
    End point description
    eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,cysC method is adjusted for age and sex. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (N = 241, 6)
    69.7 (55.9 to 82.7)
    70.2 (64.0 to 100.8)
        Change at Week 24 (N = 231, 6)
    3.8 (-4.8 to 11.2)
    3.9 (-3.3 to 13.2)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKDEPI, Creatinine) at Week 24

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    End point title
    		 Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKDEPI, Creatinine) at Week 24 [3]
    End point description
    eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,creatinine method is adjusted for age, race, and sex. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (N = 242, 6)
    54.1 (46.0 to 62.8)
    54.4 (41.7 to 81.4)
        Change at Week 24 (N = 233, 6)
    -1.8 (-6.1 to 4.9)
    -2.6 (-11.1 to -0.9)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy

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    End point title
    		 Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy
    End point description
    aGFR was directly measured using iohexol plasma clearance (CLiohexol). Participants in the Pharmacodynamic (PD) Substudy Analysis Set (enrolled in the pharmacokinetic (PK)/PD substudy, received at least 1 dose of study drug, and had baseline and at least 1 postbaseline assessment for aGFR assessed by CLiohexol) with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 2, 4, or 8; Week 24
    End point values
    		 Substudy Participants
    Number of subjects analysed
    32
    Units: mL/min
    arithmetic mean (standard deviation)
        Baseline (N = 32)
    60.1 ( 19.06 )
        Change at Week 2, 4, or 8 (N = 32)
    -0.6 ( 8.45 )
        Change at Week 24 (N = 30)
    1.4 ( 9.91 )
    Attachments
    		 Statistical Analyses
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48

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    End point title
    		 Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48
    End point description
    CTX is a biomarker of bone turnover. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 24 and 48
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    226
    6
    Units: percentage change
    median (inter-quartile range (Q1-Q3))
        Change at Week 24 (N = 226, 6)
    -3.9 (-15.8 to 10.7)
    16.9 (0.0 to 21.7)
        Change at Week 48 (N = 222, 6)
    -2.2 (-16.7 to 24.4)
    0.0 (-4.8 to 10.8)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48

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    End point title
    		 Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48
    End point description
    P1NP is a biomarker of bone turnover. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 24 and 48
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    229
    6
    Units: percentage change
    median (inter-quartile range (Q1-Q3))
        Change at Week 24 (N = 229, 6)
    -12.98 (-34.48 to 8.86)
    6.44 (-5.08 to 47.62)
        Change at Week 48 (N = 224, 6)
    -25.29 (-45.98 to 2.00)
    2.27 (-29.12 to 41.80)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144

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    End point title
    		 Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144
    End point description
    Urine RBP is a renal biomarker which is used to evaluate drug-induced kidney injury. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 24, 48, 96, and 144
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    227
    6
    Units: percentage change
    median (inter-quartile range (Q1-Q3))
        Change at Week 24 (N= 227, 6)
    -56.2 (-90.0 to -11.8)
    68.8 (-37.1 to 72.6)
        Change at Week 48 (N= 220, 6)
    -68.9 (-92.2 to -20.5)
    47.8 (13.3 to 78.9)
        Change at Week 96 (N= 212, 6)
    -64.1 (-91.4 to 9.8)
    55.0 (-10.5 to 197.0)
        Change at Week 144 (N= 187, 6)
    -63.8 (-92.4 to 4.6)
    -1.0 (-10.2 to 43.4)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144

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    End point title
    		 Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144
    End point description
    Urine beta-2-microglobulin is a renal biomarker which is used to evaluate drug-induced kidney injury. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 24, 48, 96, and 144
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    224
    6
    Units: percentage change
    median (inter-quartile range (Q1-Q3))
        Change at Week 24 (N = 224, 6)
    -70.7 (-92.6 to -11.1)
    -19.5 (-93.0 to 81.3)
        Change at Week 48 (N = 214, 6)
    -76.5 (-94.6 to -17.7)
    -59.2 (-85.0 to 34.3)
        Change at Week 96 (N = 210, 6)
    -83.6 (-96.4 to -31.1)
    -45.9 (-95.8 to 195.6)
        Change at Week 144 (N = 185, 6)
    -81.9 (-95.5 to -18.0)
    -3.6 (-66.7 to 73.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities

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    End point title
    		 Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities
    End point description
    Adverse events (AEs) and graded laboratory abnormalities occurring during the E/C/F/TAF treatment period were summarized across the participant population. A participant was counted once if they had a qualifying event. Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 240 plus 30 days
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: percentage of participants
    number (not applicable)
        Any AE
    95.5
    100.0
        Grade 3 or 4 AE
    22.3
    16.7
        AE leading to drug discontinuation
    5.0
    0
        Serious AE
    22.7
    16.7
        Grade 3 or 4 laboratory abnormality
    42.6
    66.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144

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    End point title
    		 Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144
    End point description
    The percentage of participants achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Full Analysis Set included participants who were enrolled and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, 96, and 144
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242 [4]
    6
    Units: percentage of participants
    number (not applicable)
        Week 24
    95.0
    83.3
        Week 48
    93.0
    100.0
        Week 96
    88.4
    100.0
        Week 144
    83.1
    100.0
    Notes
    [4] - For Week 144, 237 participants were analyzed (5 did not consent to be followed up after Week 96).
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameter: Cmax of TAF

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    End point title
    		 Pharmacokinetic (PK) Parameter: Cmax of TAF
    End point description
    Cmax is defined as the maximum concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set (enrolled in the PK/PD substudy, received at least 1 dose of study drug, and for whom steady-state PK parameters were available) with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: ng/mL
        arithmetic mean (standard deviation)
    269.8 ( 180.77 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Clast of TAF

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    End point title
    		 PK Parameter: Clast of TAF
    End point description
    Clast is defined as the last observable concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: ng/mL
        arithmetic mean (standard deviation)
    7.6 ( 25.73 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Tlast of TAF

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    End point title
    		 PK Parameter: Tlast of TAF
    End point description
    Tlast is defined as the time of Clast. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: hours
        median (inter-quartile range (Q1-Q3))
    4.45 (3.82 to 5.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: λz of TAF

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    End point title
    		 PK Parameter: λz of TAF
    End point description
    λz is defined as the terminal elimination rate constant. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: 1/hour
        arithmetic mean (standard deviation)
    1.764 ( 1.4521 )
    No statistical analyses for this end point

    Secondary: PK Parameter: AUCtau of TAF

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    End point title
    		 PK Parameter: AUCtau of TAF
    End point description
    AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    368.4 ( 631.20 )
    No statistical analyses for this end point

    Secondary: PK Parameter: t1/2 of TAF

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    End point title
    		 PK Parameter: t1/2 of TAF
    End point description
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: hours
        median (inter-quartile range (Q1-Q3))
    0.43 (0.37 to 0.52)
    No statistical analyses for this end point

    Secondary: PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study

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    End point title
    		 PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study
    End point description
    TFV-DP is an active phosphorylated metabolite of tenofovir alafenamide. AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants who were enrolled in the PK/PD substudy, received at least 1 dose of study drug, and for whom the steady-state PK parameter (AUCtau) of TFVDP was evaluable were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    23
    Units: μmol*h/L
        arithmetic mean (standard deviation)
    50.6 ( 55.75 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of TAF

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    End point title
    		 PK Parameter: Tmax of TAF
    End point description
    Tmax is defined as the time of Cmax. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. Participants in the PK Substudy Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
    End point values
    		 Substudy Participants
    Number of subjects analysed
    30
    Units: hours
        median (inter-quartile range (Q1-Q3))
    0.97 (0.50 to 1.98)
    No statistical analyses for this end point

    Secondary: Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144

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    End point title
    		 Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144
    End point description
    eGFR is a measurement of the kidney's ability to filter blood. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, and 144
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Baseline (N = 242, 6)
    55.6 (45.7 to 62.4)
    60.2 (45.0 to 63.2)
        Change at Week 48 (N = 225, 5)
    -0.6 (-5.4 to 5.4)
    -0.6 (-1.9 to 4.2)
        Change at Week 96 (N = 217, 6)
    0.6 (-4.6 to 7.2)
    -1.9 (-4.0 to 6.0)
        Change at Week 144 (N = 206, 6)
    1.5 (-4.8 to 7.2)
    7.0 (3.3 to 11.2)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144

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    End point title
    		 Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144
    End point description
    eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,cysC method is adjusted for age and sex. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, and 144
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (N = 241, 6)
    69.7 (55.9 to 82.7)
    70.2 (64.0 to 100.8)
        Change at Week 48 (N = 224, 5)
    1.7 (-7.3 to 12.0)
    7.3 (-0.1 to 12.2)
        Change at Week 96 (N = 216, 6)
    3.2 (-3.6 to 11.8)
    5.6 (-7.2 to 20.8)
        Change at Week 144 (N = 205, 6)
    3.1 (-4.8 to 11.8)
    3.5 (-1.8 to 22.9)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144

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    End point title
    		 Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144
    End point description
    eGFR is a measurement of the kidney's ability to filter blood. The eGFR_CKD-EPI,creatinine method is adjusted for age, race, and sex. Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, and 144
    End point values
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Number of subjects analysed
    242
    6
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (N = 242, 6)
    54.1 (46.0 to 62.8)
    54.4 (41.7 to 81.4)
        Change at Week 48 (N = 226, 5)
    -1.7 (-7.9 to 4.2)
    -3.0 (-4.9 to 0.6)
        Change at Week 96 (N = 217, 6)
    0.1 (-5.7 to 6.4)
    -3.1 (-9.5 to 2.1)
        Change at Week 144 (N = 206, 6)
    1.7 (-5.3 to 8.5)
    0.9 (-5.7 to 6.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to Week 240 plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set included participants were enrolled and 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
    Cohort 1 (Treatment-experienced)
    Reporting group description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 240 weeks in ART-experienced participants

    Reporting group title
    Cohort 2 (Treatment-naive)
    Reporting group description
    		 E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 188 weeks in ART-naive participants

    Serious adverse events
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 242 (22.73%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug dependence
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    4 / 242 (1.65%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous detachment
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 242 (1.65%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatitis c
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 242 (1.24%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 (Treatment-experienced) Cohort 2 (Treatment-naive)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    195 / 242 (80.58%)
    5 / 6 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 242 (9.92%)
    0 / 6 (0.00%)
         occurrences all number
    24
    0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 242 (8.26%)
    1 / 6 (16.67%)
         occurrences all number
    22
    1
    Chest pain
         subjects affected / exposed
    10 / 242 (4.13%)
    1 / 6 (16.67%)
         occurrences all number
    11
    1
    Peripheral swelling
         subjects affected / exposed
    8 / 242 (3.31%)
    1 / 6 (16.67%)
         occurrences all number
    8
    1
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    6 / 242 (2.48%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 242 (9.92%)
    1 / 6 (16.67%)
         occurrences all number
    27
    1
    Investigations
    Cardiac murmur
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Electrocardiogram st-t change
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Exposure to communicable disease
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 242 (8.26%)
    1 / 6 (16.67%)
         occurrences all number
    21
    2
    Dizziness
         subjects affected / exposed
    18 / 242 (7.44%)
    0 / 6 (0.00%)
         occurrences all number
    20
    0
    Paraesthesia
         subjects affected / exposed
    13 / 242 (5.37%)
    0 / 6 (0.00%)
         occurrences all number
    13
    0
    Somnolence
         subjects affected / exposed
    3 / 242 (1.24%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Migraine
         subjects affected / exposed
    2 / 242 (0.83%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    32 / 242 (13.22%)
    1 / 6 (16.67%)
         occurrences all number
    42
    2
    Nausea
         subjects affected / exposed
    22 / 242 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    28
    0
    Constipation
         subjects affected / exposed
    16 / 242 (6.61%)
    0 / 6 (0.00%)
         occurrences all number
    17
    0
    Vomiting
         subjects affected / exposed
    13 / 242 (5.37%)
    0 / 6 (0.00%)
         occurrences all number
    17
    0
    Mouth ulceration
         subjects affected / exposed
    2 / 242 (0.83%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Gingival pain
         subjects affected / exposed
    0 / 242 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    15 / 242 (6.20%)
    0 / 6 (0.00%)
         occurrences all number
    17
    0
    Dermatitis
         subjects affected / exposed
    4 / 242 (1.65%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Pruritus
         subjects affected / exposed
    4 / 242 (1.65%)
    1 / 6 (16.67%)
         occurrences all number
    5
    2
    Rash generalised
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    14 / 242 (5.79%)
    0 / 6 (0.00%)
         occurrences all number
    14
    0
    Proteinuria
         subjects affected / exposed
    3 / 242 (1.24%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    34 / 242 (14.05%)
    1 / 6 (16.67%)
         occurrences all number
    35
    1
    Back pain
         subjects affected / exposed
    27 / 242 (11.16%)
    0 / 6 (0.00%)
         occurrences all number
    30
    0
    Pain in extremity
         subjects affected / exposed
    25 / 242 (10.33%)
    2 / 6 (33.33%)
         occurrences all number
    25
    2
    Osteopenia
         subjects affected / exposed
    26 / 242 (10.74%)
    0 / 6 (0.00%)
         occurrences all number
    28
    0
    Osteoporosis
         subjects affected / exposed
    13 / 242 (5.37%)
    1 / 6 (16.67%)
         occurrences all number
    13
    1
    Tendonitis
         subjects affected / exposed
    5 / 242 (2.07%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Arthritis
         subjects affected / exposed
    3 / 242 (1.24%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 242 (16.12%)
    1 / 6 (16.67%)
         occurrences all number
    56
    2
    Bronchitis
         subjects affected / exposed
    37 / 242 (15.29%)
    1 / 6 (16.67%)
         occurrences all number
    47
    1
    Nasopharyngitis
         subjects affected / exposed
    25 / 242 (10.33%)
    0 / 6 (0.00%)
         occurrences all number
    28
    0
    Urinary tract infection
         subjects affected / exposed
    25 / 242 (10.33%)
    0 / 6 (0.00%)
         occurrences all number
    33
    0
    Sinusitis
         subjects affected / exposed
    18 / 242 (7.44%)
    0 / 6 (0.00%)
         occurrences all number
    23
    0
    Influenza
         subjects affected / exposed
    10 / 242 (4.13%)
    1 / 6 (16.67%)
         occurrences all number
    11
    1
    Hordeolum
         subjects affected / exposed
    1 / 242 (0.41%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    7 / 242 (2.89%)
    2 / 6 (33.33%)
         occurrences all number
    7
    2
    Dyslipidaemia
         subjects affected / exposed
    5 / 242 (2.07%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Vitamin d deficiency
         subjects affected / exposed
    4 / 242 (1.65%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 242 (1.24%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2013
    ● The study sample size was increased to 200 subjects ● Removed individual cohort enrollment requirements ● Clarified that the PK/PD substudy will have an enrollment target of 30 evaluable subjects ● Revised language regarding prior viral suppression (transient detectable viremia, or “blip” acceptability) ● Clarified the inclusion criteria for enrollment of subjects from Study GS-US-236-0118 into the study ● Clarified the HCV inclusion criterion ● Updated the Prior and Concomitant Medications table ● Updated the Definitions and Instructions for Pregnancy including removal of Partner Pregnancy reporting ● Added guidance for the management of potential posterior uveitis cases ● Updated the independent data monitoring committee (IDMC) trigger to 50 Cohort 1 switch subjects reaching the Week 12 visit ● Updated the table listing current Resistance Mutations by Antiretroviral Class
    21 Oct 2015
    ● Extended the duration of treatment to 144 weeks, updated objectives and endpoints to include evaluations through Week 144, updated study procedures to continue DXA scans every 24 weeks through Week 144, and added collection of urine samples at Weeks 72, 96, 120, and 144 for analysis of renal biomarkers ● Added study stopping rules for subjects in countries where GEN was not available by the date of the subject’s Week 144 visit ● Added language regarding the duration of study participation for UK subjects ● Updated the list of disallowed and discouraged medications to align with the list of prior and concomitant mediations ● Clarified the length of time that biological samples may be retained for storage ● Notified investigators of a new electronic case report form (eCRF) for “Fracture Risk Assessment” that was added to the study database to collect changes in BMD ● Removed electrocardiogram (ECG) collection for visits after Week 96 ● Updated Management of Bone Evaluation section to allow investigator discretion in managing subjects per local guidelines

    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.
    Enrollment in Cohort 2 (treatment-naive) was low, which affects the interpretation of the data.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26627107
    http://www.ncbi.nlm.nih.gov/pubmed/27673443
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