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    Clinical Trial Results:
    A Phase 3, Randomized, Active-controlled, Open-label Study to Evaluate the Efficacy, Safety and Tolerability of Switching to a Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Once-daily Single-tablet Regimen Versus Continuing the Current Regimen Consisting of a Boosted Protease Inhibitor (bPI) Combined with Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) in Virologically-suppressed, Human Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects

    Summary
    EudraCT number
    		 2014-003052-31
    Trial protocol
    		 BE   SE   GB   ES   PL   FR  
    Global end of trial date
    13 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2021
    First version publication date
    29 Oct 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TMC114IFD3013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02269917
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Sciences Ireland UC
    Sponsor organisation address
    Barnahely, Cork, Ireland, P43 FA46
    Public contact
    Clinical Registry Group, Janssen Sciences Ireland UC, clinicaltrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Sciences Ireland UC, clinicaltrialsEU@its.jnj.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
    13 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to demonstrate non-inferiority in efficacy of a darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) once-daily single-tablet regimen relative to continuing the current boosted protease inhibitor (bPI) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) in virologically-suppressed (human immunodeficiency virus-1 [HIV-1] Ribonucleic acid (RNA) less than [<] 50 copies per milliliter [copies per mL]) HIV-1 infected subjects, in regard to the proportion of virologic rebounders through Week 48, with a maximum allowable difference of 4 percent (%) (non-inferiority margin).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices (GCP) and applicable regulatory requirements. Safety was evaluated based on adverse events (AEs), clinical laboratory tests, physical examination, vital signs and bone mineral density (BMD).Safety was evaluated based on adverse events, clinical laboratory tests, physical examinations, vital signs, bone mineral density (BMD) of spine and hip and bone biomarkers in bone investigation sub-study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2015
    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
    Belgium: 52
    Country: Number of subjects enrolled
    Canada: 66
    Country: Number of subjects enrolled
    Switzerland: 39
    Country: Number of subjects enrolled
    Spain: 169
    Country: Number of subjects enrolled
    France: 97
    Country: Number of subjects enrolled
    United Kingdom: 70
    Country: Number of subjects enrolled
    Poland: 126
    Country: Number of subjects enrolled
    Sweden: 28
    Country: Number of subjects enrolled
    United States: 494
    Worldwide total number of subjects
    1141
    EEA total number of subjects
    472
    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)
    1102
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1149 subjects were enrolled in the study of which 1141 subjects received at least 1 dose of study drug and analyzed. Out of 1141 subjects, 963 subjects completed the study.

    Period 1
    Period 1 title
    BL to EOE-Test and BL to Switch-Control
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE])
    Arm description
    		 Subjects received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. After Week 48, all subjectss continued to receive D/C/F/TAF treatment (that is, initial switch to D/C/F/TAF group) up to Week 96. After Week 96, subjects were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available up to 42 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Darunavir (DRV) 800 mg/ cobicistat 150 mg/ emtricitabine 200 mg/ tenofovir alafenamide 10 mg (D/C/F/TAF) FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral tablet of D/C/F/TAF 800/150/200/10 mg FDC once daily.

    Arm title
    		 Control
    Arm description
    		 Subjects received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Boosted protease inhibitor (bPIs) (DRV or atazanavir with low-dose ritonavir [rtv] or cobicistat, or lopinavir with rtv) combined with F/TDF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subject received a single oral tablet of bPIs and F/TDF once daily.

    Number of subjects in period 1
    		D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Started
    763
    378
    Completed
    649
    352
    Not completed
    114
    26
         Adverse event, serious fatal
    4
    -
         Physician decision
    4
    -
         Consent withdrawn by subject
    32
    10
         Adverse event, non-fatal
    24
    4
         Unspecified
    19
    4
         Subject non-compliant
    4
    -
         Lost to follow-up
    25
    7
         Protocol deviation
    2
    1
    Period 2
    Period 2 title
    Switch to D/C/F/TAF (until EOE)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Switch to D/C/F/TAF
    Arm description
    		 After Week 52, subjects earlier receiving treatment with bPI+F/TDF switched to D/C/F/TAF up to Week 96. After Week 96, subjects were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available for up to 42 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    D/C/F/TAF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral tablet of D/C/F/TAF FDC once daily.

    Number of subjects in period 2 [1]
    		Switch to D/C/F/TAF
    Started
    352
    Completed
    314
    Not completed
    38
         Adverse event, serious fatal
    1
         Physician decision
    1
         Consent withdrawn by subject
    5
         Adverse event, non-fatal
    11
         Pregnancy
    2
         Unspecified
    8
         Lost to follow-up
    10
    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: Out of 378 subjects in the DRV/COBI+ F/TDF (Control) group, 352 subjects switched to D/C/F/TAF treatment after Week 52.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE])
    Reporting group description
    		 Subjects received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. After Week 48, all subjectss continued to receive D/C/F/TAF treatment (that is, initial switch to D/C/F/TAF group) up to Week 96. After Week 96, subjects were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available up to 42 months.

    Reporting group title
    Control
    Reporting group description
    		 Subjects received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.

    Reporting group values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control Total
    Number of subjects
    		 763 378 1141
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 734 368 1102
        From 65 to 84 years
    		 29 10 39
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    		 46 (19 to 75) 45 (20 to 78) -
    Title for Gender
    Units: subjects
        Female
    		 140 65 205
        Male
    		 623 313 936

    End points

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    End points reporting groups
    Reporting group title
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE])
    Reporting group description
    		 Subjects received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. After Week 48, all subjectss continued to receive D/C/F/TAF treatment (that is, initial switch to D/C/F/TAF group) up to Week 96. After Week 96, subjects were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available up to 42 months.

    Reporting group title
    Control
    Reporting group description
    		 Subjects received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.
    Reporting group title
    Switch to D/C/F/TAF
    Reporting group description
    		 After Week 52, subjects earlier receiving treatment with bPI+F/TDF switched to D/C/F/TAF up to Week 96. After Week 96, subjects were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available for up to 42 months.

    Subject analysis set title
    Darunavir 800 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received a single oral dose of DRV 800 mg as part of the DCFTAF FDC once daily up to Week 48.

    Primary: Percentage of Subjects with Virologic Rebound (Human Immunodeficiency Virus [HIV]-1 RNA Greater Than or Equal to [>=] 50 copies/mL) Cumulative Through Week 48

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    End point title
    		 Percentage of Subjects with Virologic Rebound (Human Immunodeficiency Virus [HIV]-1 RNA Greater Than or Equal to [>=] 50 copies/mL) Cumulative Through Week 48
    End point description
    Virologic rebound was defined as: confirmed plasma HIV-1 Ribonucleic Acid (RNA) level greater than or equal to (>=)50 copies per milliliter (copies/mL) up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason). Percentage of subjects with virologic rebound were reported. The intent-to-treat (ITT) analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Through Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
        number (confidence interval 95%)
    2.5 (1.5 to 3.9)
    2.1 (0.9 to 4.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 2.2

    Secondary: Percentage of Subjects with Virologic Rebound (Plasma HIV-1 RNA >=20 Copies/mL) Cumulative Through 48 Weeks

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    End point title
    		 Percentage of Subjects with Virologic Rebound (Plasma HIV-1 RNA >=20 Copies/mL) Cumulative Through 48 Weeks
    End point description
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=20 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=20 copies/mL at premature discontinuation (irrespective of reason). Percentage of subjects with virologic rebound were reported. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Through 48 Weeks
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
        number (confidence interval 95%)
    10.5 (8.4 to 12.9)
    11.4 (8.4 to 15.0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Rebound (Plasma HIV-1 RNA >=200 Copies/mL) Cumulative Through 48 Weeks

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    End point title
    		 Percentage of Subjects with Virologic Rebound (Plasma HIV-1 RNA >=200 Copies/mL) Cumulative Through 48 Weeks
    End point description
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=200 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=200 copies/mL at premature discontinuation (irrespective of reason). Percentage of subjects with virologic rebound were reported. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Through 48 Weeks
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
        number (confidence interval 95%)
    0.4 (0.1 to 1.1)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Time to Virologic Rebound at Week 48

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    End point title
    		 Percentage of Subjects with Time to Virologic Rebound at Week 48
    End point description
    Percentage of subjects with time to virologic rebound by Kaplan-Meier estimates were reported. Time to virologic rebound was calculated from baseline until the first rebound time point (that is, time point before confirmation of rebound). Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=50 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason). Here Kaplan-Meier estimates percentage of non-virologic rebound at week 96 were presented. The ITT analysis set included all subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
        number (confidence interval 95%)
    97.7 (96.4 to 98.6)
    97.8 (95.7 to 98.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuation due to AEs Through Week 48

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    End point title
    		 Percentage of Subjects Experiencing Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuation due to AEs Through Week 48
    End point description
    An AE is any untoward medical occurrence in subjects who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events were symptoms causing inability to perform usual social & functional activities. Grade 4 (Life-threatening) events were symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
    number (not applicable)
        Grade 3 AEs
    5.6
    6.3
        Grade 4 AEs
    1.2
    1.9
        SAEs
    4.6
    4.8
        Premature discontinuations due to AEs
    1.4
    1.3
    No statistical analyses for this end point

    Secondary: Change from Baseline in Serum Creatinine Levels at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Serum Creatinine Levels at Weeks 24 and 48
    End point description
    Change from baseline in serum creatinine levels at Weeks 24 and 48 was assessed. ITT analysis set included all subjects randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this endpoint; and ‘n’ specifies subjects analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    761
    378
    Units: micro mole per liter
    least squares mean (standard error)
        Change at Week 24: n= 735, 362
    1.22 ( 0.358 )
    0.88 ( 0.509 )
        Change at Week 48: n= 725, 350
    1.27 ( 0.368 )
    0.65 ( 0.530 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 1.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.646
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 1.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.646

    Secondary: Change from Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Weeks 24 and 48
    End point description
    Change from baseline in eGFRcr (by Cockcroft-Gault formula) was assessed at Weeks 24 and 48. eGFRcr according to the Cockcroft Gault formula- Male: (140 - age in years)*(weight in kilogram [kg])/72*(serum creatinine in milligram per deciliter [mg/dL])=eGFRcr (milliliter per minute [mL/min]); Female: (140 - age in years)*(weight in kg)/72*(serum creatinine in mg/dL)*0.85=eGFRcr (mL/min). ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this endpoint; and ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    761
    378
    Units: milliliter per minute (mL/min)
    least squares mean (standard error)
        Change at Week 24: n= 735, 362
    -0.38 ( 0.502 )
    0.20 ( 0.715 )
        Change at Week 48: n= 725, 350
    -0.94 ( 0.492 )
    0.20 ( 0.708 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.506
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.874
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.392
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.43
         upper limit
    		 0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.862

    Secondary: Change from Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48
    End point description
    Change from baseline in eGFRcr (by CKD-EPI) was assessed at Weeks 24 and 48. eGFRcr per CKD-EPI formula - Female: 1) Serum creatinine (Scr) less than or equal to (<=)0.7 mg/dL: 144*(Scr/0.7)^-0.329*0.993age; 2) Scr greater than (>)0.7 mg/dL: 144*(Scr/0.7)^-1.209*0.993age. Male: 1) Scr <=0.9 mg/dL: 141*(Scr/0.9)^-0.411*0.993age; 2) Scr >0.9 mg/dL: 141*(Scr/0.9)^-1.209*0.993age. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this endpoint; and ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change at Week 24: n= 735, 362
    -1.67 ( 0.359 )
    -0.75 ( 0.510 )
        Change at Week 48: n= 725, 350
    -1.97 ( 0.369 )
    -0.88 ( 0.531 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.143
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.624
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.092
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.36
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.646

    Secondary: Change from Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48
    End point description
    Change from baseline in eGFRcyst (by CKD-EPI) was assessed at Weeks 24 and 48. eGFRcyst according to the CKD-EPI formula - 1) Serum Cystatin C (Scyst) <=0.8 mg/L: 133*(Scyst/0.8)^-0.499*0.996age (*0.932 if female); 2) Scyst >0.8 mg/L: 133*(Scyst/0.8)^-1.328*0.996age (*0.932 if female). ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        eGFRcyst: Change at Week 24: n= 734, 360
    0.21 ( 0.338 )
    -0.93 ( 0.483 )
        eGFRcyst: Change at Week 48: n= 724, 351
    -0.42 ( 0.360 )
    -1.76 ( 0.517 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.054
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 2.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.034
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 2.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.63

    Secondary: Change from Baseline in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) at Weeks 24 and 48
    End point description
    Change from baseline in UACR and UPCR was assessed at Weeks 24 and 48. Lower levels of albumin or protein in the urine indicates better proximal tubular function. The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment in the study. Here, N (number of subjects analyzed) signifies subjects evaluated for this endpoint and ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    761
    378
    Units: milligram per gram (mg/g)
    median (full range (min-max))
        UACR: Baseline: n= 761, 378
    6.20 (1.4 to 632.1)
    7.14 (1.1 to 268.0)
        UACR: Change at Week 24: n= 735, 362
    -0.78 (-185.4 to 422.2)
    0.44 (-238.5 to 145.0)
        UACR: Change at Week 48: n= 723, 351
    -0.76 (-195.8 to 344.3)
    0.40 (-121.7 to 110.9)
        UPCR: Baseline: n= 758, 375
    61.56 (16.9 to 1158.1)
    62.90 (14.7 to 870.9)
        UPCR: Change at Week 24: n= 727, 357
    -14.63 (-509.6 to 734.6)
    0.07 (-359.9 to 400.8)
        UPCR: Change at Week 48: n= 710, 347
    -22.25 (-520.1 to 386.6)
    -7.37 (-368.7 to 432.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    UACR - Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    UACR - Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    UPCR - Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    UPCR - Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1139
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval

    Secondary: Change from Baseline in Urine Retinol Binding Protein to Creatinine Ratio (URBPCR) and Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Urine Retinol Binding Protein to Creatinine Ratio (URBPCR) and Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Weeks 24 and 48
    End point description
    Change from baseline in URBPCR and UB2MGCR was assessed at Weeks 24 and 48. Retinol binding protein is a marker of proximal tubular function. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this endpoint and ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    748
    371
    Units: microgram per gram (mcg/g)
    median (full range (min-max))
        URBPCR: Baseline: n= 748, 371
    126.19 (20.3 to 116216.2)
    137.16 (12.9 to 73958.4)
        URBPCR: Change at Week 24: n= 721, 356
    -30.27 (-69873.2 to 2004.4)
    7.76 (-6040.1 to 60740.4)
        URBPCR: Change at Week 48: n= 710, 344
    -27.09 (-67540.0 to 1764.3)
    19.66 (-5778.3 to 65203.3)
        UB2MGCR: Baseline: n= 736, 366
    156.85 (3.8 to 91216.2)
    172.25 (9.8 to 92740.1)
        UB2MGCR: Change at Week 24: n= 702, 348
    -72.64 (-72264.6 to 13536.2)
    12.08 (-20084.8 to 58357.6)
        UB2MGCR: Change at Week 48: n= 693, 338
    -67.02 (-72323.4 to 21190.2)
    20.24 (-22173.5 to 135576.9)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    URBPCR: Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    URBPCR: Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    UB2MGCR: Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    UB2MGCR: Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Van Elteren Test
    Confidence interval

    Secondary: Percent Change from Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Weeks 24 and 48

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    End point title
    		 Percent Change from Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Weeks 24 and 48
    End point description
    Percent change from baseline in urine FEPO4 was assessed at Weeks 24 and 48. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: Percent change
    median (full range (min-max))
        Percent change at Week 24: n= 729, 358
    3.58 (-89.4 to 1940.4)
    8.55 (-78.5 to 281.8)
        Percent change at Week 48: n=719, 346
    8.42 (-97.9 to 1430.3)
    8.57 (-76.3 to 452.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    FEPO4 - Change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.288
    Method
    		 Van Elteren Test
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    FEPO4 - Change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    1141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.148
    Method
    		 Van Elteren Test
    Confidence interval

    Secondary: Percentage of Subjects with Virologic Response based on HIV-1 RNA less Than (<)20, <50, and <200 copies/mL Threshold at Week 48 as Defined by the Food and Drug Administration (FDA) Snapshot Approach

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    End point title
    		 Percentage of Subjects with Virologic Response based on HIV-1 RNA less Than (<)20, <50, and <200 copies/mL Threshold at Week 48 as Defined by the Food and Drug Administration (FDA) Snapshot Approach
    End point description
    Percentage of subjects with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 48 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic response was defined as HIV-1 RNA <20/50/200 copies/mL (observed case). The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
    number (confidence interval 95%)
        <20 copies/mL
    89.8 (87.4 to 91.8)
    88.4 (84.7 to 91.4)
        <50 copies/mL
    94.9 (93.1 to 96.3)
    93.7 (90.7 to 95.9)
        <200 copies/mL
    95.0 (93.2 to 96.5)
    94.2 (91.3 to 96.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Response based on HIV-1 RNA <20, <50, and <200 copies/mL Threshold at Week 48 as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm

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    End point title
    		 Percentage of Subjects with Virologic Response based on HIV-1 RNA <20, <50, and <200 copies/mL Threshold at Week 48 as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm
    End point description
    Percentage of subjects with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 48 using TLOVR algorithm approach. TLOVR was defined as sustained HIV-1 RNA <20/50/200 copies/mL. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: percentage of subjects
    number (confidence interval 95%)
        <20 copies/mL
    86.0 (83.3 to 88.4)
    83.6 (79.5 to 87.2)
        <50 copies/mL
    93.7 (91.7 to 95.3)
    92.9 (89.8 to 95.2)
        <200 copies/mL
    95.4 (93.7 to 96.8)
    94.7 (91.9 to 96.7)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cluster of Differentiation 4 plus (CD4+) Cell Count at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Cluster of Differentiation 4 plus (CD4+) Cell Count at Weeks 24 and 48
    End point description
    Change from baseline in CD4+ cell count was assessed at Weeks 24 and 48. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this endpoint and ‘n’ specifies those subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    763
    378
    Units: cells per cubic millimeter (cells/mm^3)
    arithmetic mean (standard error)
        Baseline: n= 763, 378
    653.3 ( 9.12 )
    641.7 ( 13.15 )
        Change at Week 24: n= 731, 362
    14.3 ( 5.99 )
    8.5 ( 7.76 )
        Change at Week 48: n= 722, 351
    21.0 ( 5.97 )
    9.1 ( 8.41 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Adherence of Greater Than (>)95 Percent (%) (Approach 1) Through Week 48

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    End point title
    		 Percentage of Subjects with Treatment Adherence of Greater Than (>)95 Percent (%) (Approach 1) Through Week 48
    End point description
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative through Week 48 (Approach 1). The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Through Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    215
    102
    Units: percentage of subjects
        number (not applicable)
    91.6
    85.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Adherence of >95% (Approach 2) Through Week 48

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    End point title
    		 Percentage of Subjects with Treatment Adherence of >95% (Approach 2) Through Week 48
    End point description
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative treatment adherence up to time point where not more than one bottle was missing, or if available, through Week 48, whichever came sooner (Approach 2). The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates the number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Through Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    631
    268
    Units: percentage of subjects
        number (not applicable)
    82.8
    80.9
    No statistical analyses for this end point

    Secondary: Number of Subjects with Resistance to Study Drug

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    End point title
    		 Number of Subjects with Resistance to Study Drug
    End point description
    HIV-1 genotypes were analyzed from samples of subjects with confirmed virologic rebound (virologic rebound was defined as: confirmed HIV-1 RNA >=50 copies/mL up to, and including the upper bound of the Week 48 window) and with HIV-1 RNA value greater than or equal to (>=)400 copies/mL or who discontinued with last HIV-1 RNA >=400 copies/mL. Number of subjects who developed resistance to any of the study drug was determined. The ITT population with confirmed virologic rebound and with HIV-1 RNA value >=400 copies/mL was analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    19
    8
    Units: Subjects
    1
    3
    No statistical analyses for this end point

    Secondary: Predose (trough) Plasma Concentration (C0h) of Darunavir

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    End point title
    		 Predose (trough) Plasma Concentration (C0h) of Darunavir
    End point description
    Predose (trough) plasma concentration (C0h) of darunavir was determined. Pharmacokinetic (PK) data was only analyzed for subjects in the D/C/F/TAF group as per planned analysis. The PK analysis set included all subjects randomized to D/C/F/TAF group and received at least 1 dose of study drug in study, and for whom plasma concentration data of any analytes of interest were available. Here ‘n’ specifies subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Predose at Weeks 2, 4, 8, 12, 24, 36, and 48
    End point values
    		 Darunavir 800 mg
    Number of subjects analysed
    750
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Week 2: n=130
    1775.29 ( 1698.84 )
        Week 4: n= 110
    1732.00 ( 1389.44 )
        Week 8: n=104
    1910.30 ( 1501.94 )
        Week 12: n=114
    1643.38 ( 1328.41 )
        Week 24: n=112
    2022.99 ( 1965.64 )
        Week 36: n=100
    1806.37 ( 1669.43 )
        Week 48: n=126
    1899.79 ( 1833.09 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) Levels at Weeks 24 and 48

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    End point title
    		 Percent Change from Baseline in Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) Levels at Weeks 24 and 48
    End point description
    Percent change from baseline in bone biomarkers: P1NP and CTX was assessed at Weeks 24 and 48. The bone investigation substudy (BIS) analysis set included all subjects who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    209
    108
    Units: percent change
    arithmetic mean (standard error)
        P1NP: Percent change at Week 24: n= 195, 99
    -22.971 ( 1.8818 )
    -0.027 ( 2.7325 )
        P1NP: Percent change at Week 48: n= 191, 98
    -26.752 ( 1.8960 )
    -3.751 ( 2.6988 )
        CTX: Percent change at Week 24: n= 190, 97
    -16.772 ( 2.2575 )
    16.312 ( 3.8855 )
        CTX: Percent change at Week 48: n= 185, 98
    -10.517 ( 3.2325 )
    5.433 ( 4.1118 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Parathyroid Hormone (PTH) at Weeks 24 and 48

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    End point title
    		 Percent Change from Baseline in Parathyroid Hormone (PTH) at Weeks 24 and 48
    End point description
    Percent change from baseline in bone biomarker: PTH was assessed at Weeks 24 and 48. The bone investigation substudy (BIS) analysis set included all subjects who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    209
    108
    Units: percent change
    arithmetic mean (standard error)
        Percent change at Week 24: n= 199, 102
    -3.092 ( 2.5941 )
    12.034 ( 4.1777 )
        Percent change at Week 48: n= 193, 103
    -4.510 ( 2.5375 )
    9.436 ( 4.4784 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in 25-hydroxy Vitamin D at Weeks 24 and 48

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    End point title
    		 Percent Change from Baseline in 25-hydroxy Vitamin D at Weeks 24 and 48
    End point description
    Percent change from baseline in bone biomarker: 25-hydroxy vitamin D was assessed at Weeks 24 and 48. BIS analysis set included all subjects who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    209
    108
    Units: percent change
    arithmetic mean (standard error)
        Percent change at Week 24: n= 146, 72
    -3.0 ( 5.06 )
    4.2 ( 6.13 )
        Percent change at Week 48: n= 142, 72
    25.2 ( 5.51 )
    24.9 ( 7.46 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Spine and Hip Bone Mineral Density (BMD) at Weeks 24 and 48

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    End point title
    		 Percent Change from Baseline in Spine and Hip Bone Mineral Density (BMD) at Weeks 24 and 48
    End point description
    Percent change from baseline in spine and hip BMD was assessed at Weeks 24 and 48. BIS analysis set included all subjects who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    209
    108
    Units: percent change
    least squares mean (standard error)
        Spine BMD: Percent change at Week 24: n= 192, 97
    1.55 ( 0.276 )
    0.18 ( 0.342 )
        Spine BMD: Percent change at Week 48: n= 192, 101
    2.06 ( 0.324 )
    0.01 ( 0.391 )
        Hip BMD: Percent change at Week 24: n= 184, 93
    0.91 ( 0.230 )
    0.00 ( 0.279 )
        Hip BMD: Percent change at Week 48: n=
    1.62 ( 0.244 )
    -0.08 ( 0.288 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Spine BMD: Percent change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.697
         upper limit
    		 2.037
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Spine BMD: Percent change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.277
         upper limit
    		 2.814
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Hip BMD: Percent change at Week 24
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.366
         upper limit
    		 1.436
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.272
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Hip BMD: Percent change at Week 48
    Comparison groups
    D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) v Control
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.144
         upper limit
    		 2.248
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28

    Secondary: Change from Baseline in Bone Mineral Density (BMD) T-Score at Weeks 24 and 48

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    End point title
    		 Change from Baseline in Bone Mineral Density (BMD) T-Score at Weeks 24 and 48
    End point description
    Change from baseline in spine, hip, and femoral neck BMD T-Score was assessed at Week (Wk) 24 and 48. T-score values >= -1.0 were considered normal, T-score values < -1.0 to -2.5 indicate osteopenia and T-score values < -2.5 indicate osteoporosis. BIS analysis set included all subjects who were randomized and received at least 1 dose of study drug in the study, and had at least one postbaseline value for biomarker data. Here ‘n’ specifies subjects who were analyzed for this endpoint at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 48
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    209
    108
    Units: units on a scale
    arithmetic mean (standard error)
        Spine BMD T-score: Baseline: n= 206, 107
    -0.713 ( 0.0850 )
    -0.467 ( 0.1260 )
        Spine BMD T-score: Change at Wk 24: n= 192, 97
    0.102 ( 0.0172 )
    -0.033 ( 0.0253 )
        Spine BMD T-score: Change at Wk 48: n= 192, 101
    0.132 ( 0.0217 )
    -0.063 ( 0.0264 )
        Hip BMD T-score: Baseline: n=204, 104
    -0.575 ( 0.0643 )
    -0.484 ( 0.0839 )
        Hip BMD T-score: Change at We 24: n=184, 93
    0.037 ( 0.0108 )
    -0.024 ( 0.0144 )
        Hip BMD T-score: Change at Wk 48: n=188, 97
    0.095 ( 0.0122 )
    -0.016 ( 0.0139 )
        Femoral Neck BMD T-score:Baseline: n=204,104
    -0.782 ( 0.0625 )
    -0.699 ( 0.0899 )
        Femoral Neck BMD T-score:Change at Wk 24: n=184,93
    0.019 ( 0.0128 )
    -0.044 ( 0.0183 )
        Femoral Neck BMD T-score:Change at Wk 48: n=188,97
    0.039 ( 0.0146 )
    -0.039 ( 0.0214 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Rebound (HIV-1 RNA >=20 copies/mL) Cumulative Through Week 96

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    End point title
    		 Percentage of Subjects with Virologic Rebound (HIV-1 RNA >=20 copies/mL) Cumulative Through Week 96 [1]
    End point description
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=20 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=20 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=20 copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Percentage of subjects with virologic rebound were reported. Intent-to-treat (ITT) analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Through Week 96
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: percentage of subjects
        number (confidence interval 95%)
    13.8 (11.4 to 16.4)
    8.8 (6.1 to 12.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Rebound (HIV-1 RNA >=50 copies/mL) Cumulative Through Week 96

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    End point title
    		 Percentage of Subjects with Virologic Rebound (HIV-1 RNA >=50 copies/mL) Cumulative Through Week 96 [2]
    End point description
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=50 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=50copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Percentage of subjects with virologic rebound were reported. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Through Week 96
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: percentage of subjects
        number (confidence interval 95%)
    3.1 (2.0 to 4.6)
    2.3 (1.0 to 4.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Rebound (HIV-1 RNA >=200 copies/mL) Cumulative Through Week 96

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    End point title
    		 Percentage of Subjects with Virologic Rebound (HIV-1 RNA >=200 copies/mL) Cumulative Through Week 96 [3]
    End point description
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=200 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=200 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=200 copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Percentage of subjects with virologic rebound were reported. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Through Week 96
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: percentage of subjects
        number (confidence interval 95%)
    0.5 (0.1 to 1.3)
    0.6 (0.6 to 2.0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Time to Virologic Rebound at Week 96

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    End point title
    		 Percentage of Subjects with Time to Virologic Rebound at Week 96 [4]
    End point description
    Percentage of subjects with time to virologic rebound by Kaplan-Meier estimates were reported. Time to virologic rebound (confirmed plasma HIV-1 RNA level >=50 copies/mL up to and including Week 96, last available on-treatment [single] HIV-1 RNA >=50 copies/mL at premature discontinuation [irrespective of reason], and last available on-treatment HIV-1 RNA >=50 copies/mL at the study cutoff of Week 96) was calculated from reference until the first rebound time point (that is, time point before confirmation of rebound) up to Week 96 visit. Here Kaplan-Meier estimates percentage of non-virologic rebound at week 96 are presented. The ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: percentage of subjects
        number (confidence interval 95%)
    96.7 (95.1 to 97.8)
    97.8 (95.4 to 98.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Response based on HIV-1 RNA <20, <50, and <200 copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach

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    End point title
    		 Percentage of Subjects with Virologic Response based on HIV-1 RNA <20, <50, and <200 copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach [5]
    End point description
    Percentage of subjects with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 96 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic response was defined as having last available HIV-1 RNA <20/50/200 copies/mL (observed case). ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96])
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: Percentage of Subjects
    number (confidence interval 95%)
        <20 copies/mL
    85.3 (82.6 to 87.8)
    89.8 (86.1 to 92.7)
        <50 copies/mL
    90.7 (88.4 to 92.7)
    93.8 (90.7 to 96)
        <200 copies/mL
    91.2 (89.0 to 93.1)
    95.5 (92.7 to 97.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Response based on HIV-1 RNA <20, <50, and <200 copies/mL Threshold at Week 96 as Defined by the TLOVR Algorithm

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    End point title
    		 Percentage of Subjects with Virologic Response based on HIV-1 RNA <20, <50, and <200 copies/mL Threshold at Week 96 as Defined by the TLOVR Algorithm [6]
    End point description
    Percentage of subjects with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 96 using TLOVR algorithm approach. TLOVR was defined as sustained HIV-1 RNA <20/50/200 copies/mL. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96])
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: Percentage of subjects
    number (confidence interval 95%)
        <20 copies/mL
    79.6 (76.5 to 82.4)
    88.1 (84.2 to 91.3)
        <50 copies/mL
    89.6 (87.3 to 91.7)
    94.3 (91.4 to 96.5)
        <200 copies/mL
    91.7 (89.6 to 93.6)
    95.7 (93.1 to 97.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Virologic Failure based on HIV-1 RNA >=20, >=50, and >=200 copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach

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    End point title
    		 Percentage of Subjects with Virologic Failure based on HIV-1 RNA >=20, >=50, and >=200 copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach [7]
    End point description
    Percentage of subjects with virologic failure based on HIV-1 RNA >=20, >=50, and >=200 copies/mL threshold were analyzed at Week 96 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic failure was defined by the FDA snapshot approach as having last available HIV-1 RNA >=20/50/200 copies/mL at Week 96; virologic failure - leading to discontinuation; virologic failure - discontinued due to other reason and last available HIV-1 RNA >=20/50/200 copies/mL. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, 99999 refers that confidential interval was not calculated as none of the subjects had HIV RNA <200 copies/mL.
    End point type
    Secondary
    End point timeframe
    Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96])
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: Percentage of subjects
    number (confidence interval 95%)
        <20 copies/mL
    6.8 (5.1 to 8.8)
    6.0 (3.7 to 9.0)
        <50 copies/mL
    1.2 (0.5 to 2.2)
    1.7 (0.6 to 3.7)
        <200 copies/mL
    0.3 (0.0 to 0.9)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Reference in CD4+ Cell Count at Week 96

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    End point title
    		 Change from Reference in CD4+ Cell Count at Week 96 [8]
    End point description
    Change from reference in CD4+ cell count was assessed at Week 96. The change from reference in CD4+ count at a given time point is defined as: CD4+ at a given time point minus reference CD4+. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Based on NC=F analysis with values after discontinuation imputed with the reference value. Other (intermittent) missing values are imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF (Comprising 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52])
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: Cells per cubic millimeter (cells/mm^3)
        least squares mean (standard error)
    32.07 ( 8.0 )
    13.07 ( 10.7 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Resistance to Study Drug Through Week 96

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    End point title
    		 Number of Subjects with Resistance to Study Drug Through Week 96
    End point description
    HIV-1 genotypes were analyzed from samples of subjects with confirmed virologic rebound in case they had HIV-1 RNA values >=400 copies/mL at failure or at later time points including subjects who discontinued with last HIV-1 RNA>=400 copies/mL. Virologic rebound: confirmed plasma HIV-1 RNA level >=20 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA>=20 copies/mL at premature discontinuation (irrespective of reason) and last available on-treatment HIV-1 RNA>=20 copies/mL at study cutoff of Week 96. Number of subjects who developed resistance to any study drug (DRV, FTC and TFV/TAF) were reported. ITT analysis set: all randomized subjects and received at least one dose of study treatment in study. Here, N (number of subjects analyzed) signifies total number of subjects with screening/baseline and endpoint genotype. Due to low proportion of rebounders of which majority had low viral load values, few samples were eligible for postbaseline genotyping.
    End point type
    Secondary
    End point timeframe
    Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF Control
    Number of subjects analysed
    9
    7
    3
    Units: Subjects
        DRV resistance-associated mutations (RAMs)
    0
    0
    0
        TFV RAMs
    0
    0
    0
        FTC RAMs
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Adherence of >95 (Approach 1) Through 96 Weeks

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    End point title
    		 Percentage of Subjects with Treatment Adherence of >95 (Approach 1) Through 96 Weeks [9]
    End point description
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative through Week 96 (Approach 1). ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates the number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    379
    236
    Units: Percentage of subjects
        number (not applicable)
    91.6
    87.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Adherence of >95% (Approach 2) Through 96 Weeks

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    End point title
    		 Percentage of Subjects with Treatment Adherence of >95% (Approach 2) Through 96 Weeks [10]
    End point description
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative treatment adherence up to time point where not more than one bottle was missing, or if available, through Week 96, whichever came sooner (Approach 2). ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, 'N' (number of subjects analyzed) indicates the number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    646
    320
    Units: Percentage of subjects
        number (not applicable)
    82.8
    80.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing Grade 3 and 4 AEs, SAEs, and Premature Discontinuation due to AEs Through 96 Weeks

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    End point title
    		 Percentage of Subjects Experiencing Grade 3 and 4 AEs, SAEs, and Premature Discontinuation due to AEs Through 96 Weeks [11]
    End point description
    AE is any untoward medical occurrence in subjects who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events were symptoms causing inability to perform usual social & functional activities. Grade 4 (Life-threatening) events were symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize subject and/or may require medical or surgical intervention to prevent one of the outcomes listed above. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    763
    352
    Units: Percentage of subjects
    number (not applicable)
        Grade 3 AEs
    10.5
    6.3
        Grade 4 AEs
    2.4
    1.1
        SAEs
    8.7
    6.0
        Premature discontinuations due to AEs
    2.2
    2.0
    No statistical analyses for this end point

    Secondary: Change from Reference in Serum Creatinine Levels at Week 96

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    End point title
    		 Change from Reference in Serum Creatinine Levels at Week 96 [12]
    End point description
    Change from reference in serum creatinine levels at Week 96 was assessed. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis. For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference. The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    692
    336
    Units: Micro mole per liter
        median (full range (min-max))
    0.0 (-35 to 44)
    0.0 (-45 to 29)
    No statistical analyses for this end point

    Secondary: Change from Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Week 96

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    End point title
    		 Change from Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Week 96 [13]
    End point description
    Change from reference in eGFRcr (by Cockcroft-Gault formula) was assessed at Week 96. eGFRcr according to the Cockcroft Gault formula- Male: (140 - age in years)*(weight in kilogram [kg])/72*(serum creatinine in milligram per deciliter [mg/dL])=eGFRcr (milliliter per minute [mL/min]); Female: (140 - age in years)*(weight in kg)/72*(serum creatinine in mg/dL)*0.85=eGFRcr (mL/min). For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment in the study. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    692
    336
    Units: Milliliter per minute (mL/min)
        median (full range (min-max))
    -0.9 (-65 to 58)
    0.0 (-44 to 157)
    No statistical analyses for this end point

    Secondary: Change from Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (by CKD-EPI) at Week 96

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    End point title
    		 Change from Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (by CKD-EPI) at Week 96 [14]
    End point description
    Change from reference in eGFRcr (by CKD-EPI) was assessed at Week 96. eGFRcr per CKD-EPI formula - Female: 1) Serum creatinine (Scr) less than or equal to (<=)0.7 mg/dL: 144*(Scr/0.7)^-0.329*0.993^age; 2) Scr greater than (>)0.7 mg/dL: 144*(Scr/0.7)^-1.209*0.993^age. Male: 1) Scr <=0.9 mg/dL: 141* (Scr/0.9)^-0.411*0.993^age; 2) Scr >0.9 mg/dL: 141*(Scr/0.9)^-1.209*0.993^age. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and subjects at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    692
    336
    Units: mL/min/1.73 m^2
        median (full range (min-max))
    -1.3 (-37 to 35)
    -0.7 (-31 to 49)
    No statistical analyses for this end point

    Secondary: Change from Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (by CKD-EPI) at Week 96

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    End point title
    		 Change from Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (by CKD-EPI) at Week 96 [15]
    End point description
    Change from reference in eGFRcyst (by CKD-EPI) was assessed at Week 96. eGFRcyst according to the CKD-EPI formula - 1) Serum Cystatin C (Scyst) <=0.8 mg/L: 133*(Scyst/0.8)^-0.499*0.996^age (*0.932 if female); 2) Scyst >0.8 mg/L: 133*(Scyst/0.8)^-1.328*0.996^age (*0.932 if female). For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and subjects at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    686
    332
    Units: mL/min/1.73 m^2
        median (full range (min-max))
    -0.9 (-42 to 30)
    1.0 (-30 to 105)
    No statistical analyses for this end point

    Secondary: Change from Reference in UACR at Week 96

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    End point title
    		 Change from Reference in UACR at Week 96 [16]
    End point description
    Change from reference in UACR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    694
    334
    Units: Milligram per gram (mg/g)
        median (full range (min-max))
    -0.63 (-209.3 to 2019.7)
    -0.93 (-234.6 to 13230.9)
    No statistical analyses for this end point

    Secondary: Change from Reference in URBPCR at Week 96

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    End point title
    		 Change from Reference in URBPCR at Week 96 [17]
    End point description
    Change from reference in URBPCR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment in the study. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    675
    331
    Units: Microgram per gram (mcg/g)
        median (full range (min-max))
    -25.08 (-61980.5 to 1393.0)
    -39.07 (-82240.7 to 869.9)
    No statistical analyses for this end point

    Secondary: Change from Reference in UPCR at Week 96

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    End point title
    		 Change from Reference in UPCR at Week 96 [18]
    End point description
    Change from reference in UPCR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    675
    331
    Units: Milligram per gram (mg/g)
        median (full range (min-max))
    -22.23 (-533.3 to 2314.7)
    -12.81 (-722.1 to 453.1)
    No statistical analyses for this end point

    Secondary: Change from Reference in UB2MGCR at Week 96

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    End point title
    		 Change from Reference in UB2MGCR at Week 96 [19]
    End point description
    Change from reference in UB2MGCR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    664
    332
    Units: Microgram per gram (mcg/g)
        median (full range (min-max))
    -68.22 (-71549.3 to 7433.1)
    -110.31 (-152500.2 to 12288.4)
    No statistical analyses for this end point

    Secondary: Percent Change from Reference in FEPO4 at Week 96

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    End point title
    		 Percent Change from Reference in FEPO4 at Week 96
    End point description
    Percent change from reference in FEPO4 at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Control
    Number of subjects analysed
    688
    334
    Units: Percent change
        median (full range (min-max))
    4.15 (-88.0 to 524.8)
    -3.19 (-77.9 to 547.8)
    No statistical analyses for this end point

    Secondary: Percent change From Reference in Levels of Serum P1NP at Week 96

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    End point title
    		 Percent change From Reference in Levels of Serum P1NP at Week 96 [20]
    End point description
    Percent change from reference in serum P1NP levels at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). BIS analysis set included all subjects who were randomized, received at least 1 dose of study drug in study and had at least one post-baseline value for either biomarker/BMD data. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    183
    96
    Units: percent change
        arithmetic mean (standard error)
    -19.899 ( 2.2151 )
    -18.466 ( 3.1169 )
    No statistical analyses for this end point

    Secondary: Percent change From Reference in Levels of Serum CTX at Week 96

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    End point title
    		 Percent change From Reference in Levels of Serum CTX at Week 96 [21]
    End point description
    Percent change from reference in serum CTX at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). BIS analysis set included all subjects who were randomized, received at least 1 dose of study drug in study and had at least one post-baseline value for either biomarker/BMD data. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    178
    98
    Units: percent change
        arithmetic mean (standard error)
    -10.192 ( 3.0592 )
    -21.755 ( 3.4926 )
    No statistical analyses for this end point

    Secondary: Percent change From Reference in Levels of PTH at Week 96

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    End point title
    		 Percent change From Reference in Levels of PTH at Week 96 [22]
    End point description
    Percent change from reference in PTH at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). BIS analysis set included all subjects who were randomized, received at least 1 dose of study drug in study and had at least one post-baseline value for either biomarker/BMD data. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    169
    97
    Units: percent change
        arithmetic mean (standard error)
    -17.171 ( 2.6774 )
    -20.466 ( 3.2559 )
    No statistical analyses for this end point

    Secondary: Percent change From Reference in Levels of 25-OH Vitamin D at Week 96

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    End point title
    		 Percent change From Reference in Levels of 25-OH Vitamin D at Week 96 [23]
    End point description
    Percent change from reference in 25-OH Vitamin D at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2). BIS analysis set included all subjects who were randomized, received at least 1 dose of study drug in study and had at least one post-baseline value for either biomarker/BMD data. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    141
    96
    Units: percent change
        arithmetic mean (standard error)
    24.6 ( 5.16 )
    -1.9 ( 3.33 )
    No statistical analyses for this end point

    Secondary: Percent Change From Reference in Hip and Spine BMD at Week 96

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    End point title
    		 Percent Change From Reference in Hip and Spine BMD at Week 96 [24]
    End point description
    The BMD is the amount of mineral in gram per square centimeter of bone, which was assessed by DXA scan. Positive values are "best values" and negative values are "worst values" of change. Percent change from reference in hip and spine BMD was assessed. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2) BIS analysis set included all subjects who were randomized, received at least 1 dose of study drug in study and had at least one post-baseline value for either biomarker/BMD data. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this outcome measure; and ‘n’ specifies subjects analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    173
    99
    Units: Percent change
    arithmetic mean (standard error)
        Hip region BMD: n= 164, 96
    0.0173 ( 0.00217 )
    0.0108 ( 0.00328 )
        Spine region BMD: n= 173, 99
    0.0193 ( 0.00286 )
    0.0279 ( 0.00381 )
    No statistical analyses for this end point

    Secondary: Change From Reference in BMD T-score of Hip and Spine at Week 96

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    End point title
    		 Change From Reference in BMD T-score of Hip and Spine at Week 96 [25]
    End point description
    BMD status was assessed using BMD T-scores; normal bone status was defined by a BMD T-score >= -1, osteopenia by a T-score >= -2.5 to <-1.0, and osteoporosis by a T-score <-2.5. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2) BIS analysis set included all subjects who were randomized, received at least 1 dose of study drug in study and had at least one post-baseline value for either biomarker/BMD data. Here, 'N' (number of subjects analyzed) signifies subjects evaluated for specified categories.
    End point type
    Secondary
    End point timeframe
    From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    209
    105
    Units: units on a scale
    arithmetic mean (standard error)
        Hip region BMD: n= 164, 96
    0.122 ( 0.0154 )
    0.077 ( 0.0230 )
        Spine region BMD: n= 173, 99
    0.176 ( 0.0259 )
    0.255 ( 0.0339 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Time to Protocol-defined Virologic Rebound by Kaplan-Meier Estimates

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    End point title
    		 Percentage of Subjects with Time to Protocol-defined Virologic Rebound by Kaplan-Meier Estimates [26]
    End point description
    Percentage of subjects with time to protocol-defined virologic rebound by kaplan-meier estimates were reported. Virologic rebound is defined as subjects who show confirmed HIV-1 RNA >=50 copies/mL, or for which the last available (single) HIV-1 RNA value on treatment was >=50 copies/mL. Time to protocol-defined virologic rebound is defined as the time (in weeks) calculated from reference until the first rebound time point (time point before confirmation of rebound). Here, Kaplan-Meier estimates (%) of non-virologic rebound at every 6 months interval are presented. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this outcome measure; and ‘n’ specifies subjects analyzed for specified timepoints.
    End point type
    Secondary
    End point timeframe
    Week 96 to end of extension (at every 6 months, up to 42 months)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    671
    323
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 96: n= 671, 323
    100 (100 to 100)
    100 (100 to 100)
        Week 96 + 6 months: n= 638, 308
    99.4 (98.4 to 99.8)
    100 (100 to 100)
        Week 96 + 12 months: n= 515, 248
    98.0 (96.5 to 98.9)
    98.5 (96.0 to 99.4)
        Week 96 + 18 months: n= 325, 159
    97.6 (95.9 to 98.6)
    98.1 (95.4 to 99.2)
        Week 96 + 24 months: n= 150, 68
    97.1 (94.9 to 98.3)
    96.5 (92.3 to 98.4)
        Week 96 + 30 months: n= 55, 28
    95.3 (91.3 to 97.5)
    96.5 (92.3 to 98.4)
        Week 96 + 36 months: n= 26, 8
    92.4 (83 to 96.7)
    96.5 (92.3 to 98.4)
        Week 96 + 42 months: n= 2, 0
    92.4 (83.0 to 96.7)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Time to Treatment Failure by Kaplan-Meier Estimates

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    End point title
    		 Percentage of Subjects with Time to Treatment Failure by Kaplan-Meier Estimates [27]
    End point description
    Percentage of subjects with time to treatment failure by Kaplan-Meier Estimates were reported. Treatment failure was defined as having either protocol-defined virologic rebound or having discontinued for reasons other than alternate access to D/C/F/TAF (or other antiretroviral [ARV]). The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this outcome measure; and ‘n’ specifies subjects analyzed for specified timepoints.
    End point type
    Secondary
    End point timeframe
    Week 96 to end of extension (at every 6 months, up to 42 months)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    680
    326
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 96: n= 680, 326
    100 (100 to 100)
    100 (100 to 100)
        Week 96 + 6 months: n= 646, 311
    98.1 (96.7 to 98.9)
    98.5 (96.3 to 99.4)
        Week 96 + 12 months: n= 532, 261
    94.3 (92.2 to 95.9)
    95.4 (92.3 to 97.2)
        Week 96 + 18 months: n= 348, 177
    91.6 (89.0 to 93.6)
    92.2 (88.3 to 94.8)
        Week 96 + 24 months: n= 163, 71
    89.4 (86.1 to 91.9)
    89.7 (85.0 to 93.0)
        Week 96 + 30 months: n= 62, 32
    87.0 (82.7 to 90.4)
    88.1 (82.0 to 92.2)
        Week 96 + 36 months: n= 32, 12
    84.9 (78.2 to 89.6)
    82.6 (67.4 to 91.1)
        Week 96 + 42 months: n= 2, 0
    81.7 (71.9 to 88.4)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with HIV RNA <50, <20, <200 Copies/mL Post Week 96 to End of Extension

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    End point title
    		 Percentage of Subjects with HIV RNA <50, <20, <200 Copies/mL Post Week 96 to End of Extension [28]
    End point description
    Percentage of subjects with HIV RNA <50, <20, <200 copies/mL post Week 96 to end of extension were reported. The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment in the study. Here, N (number of subjects analyzed) indicates number of subjects evaluable for this outcome measure; and ‘n’ specifies subjects analyzed for specified timepoints.
    End point type
    Secondary
    End point timeframe
    Week 96 to end of extension (up to 42 months)
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    688
    334
    Units: percentage of subjects
    number (confidence interval 95%)
        Week 96 + 6 months (<50 copies/mL) n= 688, 334
    97.8 (96.4 to 98.8)
    97.9 (95.7 to 99.2)
        Week 96 + 12 months (<50 copies/mL) n= 611, 302
    98.4 (97.0 to 99.2)
    97.4 (94.8 to 98.8)
        Week 96 + 18 months (<50 copies/mL) n= 461, 225
    99.6 (98.4 to 99.9)
    98.7 (96.2 to 99.7)
        Week 96 + 24 months (<50 copies/mL) n= 280, 134
    99.3 (97.4 to 99.9)
    98.5 (94.7 to 99.8)
        Week 96 + 30 months (<50 copies/mL) n= 135, 64
    99.3 (95.9 to 100)
    100 (94.4 to 100)
        Week 96 + 36 months (<50 copies/mL) n= 52, 26
    98.1 (89.7 to 100)
    100 (86.8 to 100)
        Week 96 + 42 months (<50 copies/mL) n= 16, 7
    100 (79.4 to 100)
    100 (59.0 to 100)
        Week 96 + 6 months (<200 copies/mL) n= 688, 334
    99.1 (98.1 to 99.7)
    99.7 (98.3 to 100)
        Week 96 + 12 months (<200 copies/mL) n= 611, 302
    99.3 (98.3 to 99.8)
    98.7 (96.6 to 99.6)
        Week 96 + 18 months (<200 copies/mL) n= 461, 225
    100 (99.2 to 100)
    99.1 (96.8 to 99.9)
        Week 96 + 24 months (<200 copies/mL) n= 280, 134
    99.6 (98 to 100)
    99.3 (95.9 to 100)
        Week 96 + 30 months (<200 copies/mL) n= 135, 64
    100 (97.3 to 100)
    100 (94.4 to 100)
        Week 96 + 36 months (<200 copies/mL) n= 52, 26
    100 (93.2 to 100)
    100 (86.8 to 100)
        Week 96 + 42 months (<200 copies/mL) n= 16, 7
    100 (79.4 to 100)
    100 (59 to 100)
        Week 96 + 6 months (<20 copies/mL) n= 688, 334
    91.4 (89.1 to 93.4)
    93.4 (90.2 to 95.8)
        Week 96 + 12 months (<20 copies/mL) n= 611, 302
    93.9 (91.7 to 95.7)
    91.4 (87.6 to 94.3)
        Week 96 + 18 months (<20 copies/mL) n= 461, 225
    96.1 (93.9 to 97.7)
    92.9 (88.7 to 95.9)
        Week 96 + 24 months (<20 copies/mL) n= 280, 134
    96.1 (93.1 to 98.0)
    95.5 (90.5 to 98.3)
        Week 96 + 30 months (<20 copies/mL) n= 135, 64
    95.6 (90.6 to 98.4)
    92.2 (82.7 to 97.4)
        Week 96 + 36 months (<20 copies/mL) n= 52, 26
    94.2 (84.1 to 98.8)
    96.2 (80.4 to 99.9)
        Week 96 + 42 months (<20 copies/mL) n= 16, 7
    93.8 (69.8 to 99.8)
    100 (59 to 100)
    No statistical analyses for this end point

    Secondary: CD4+ Cell Count Post-Week 96 to end of Extension

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    End point title
    		 CD4+ Cell Count Post-Week 96 to end of Extension [29]
    End point description
    The immunologic change was determined by Cluster of CD4+ cell count. CD4+ cell count post-Week 96 to end of extension were assessed. The ITT analysis set included all the subjects who were randomized and received at least one dose of study treatment in the study. Here, N (number of subjects analyzed) signifies subjects evaluated for this outcome measure and n (number analyzed) signifies subjects analyzed for this outcome measure at specified category.
    End point type
    Secondary
    End point timeframe
    Week 96 to end of extension (up to 42 months)
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    682
    332
    Units: Cells per cubic millimeter (cells/mm^3)
    arithmetic mean (standard error)
        Week 96 + 6 months: n= 682, 332
    706.4 ( 10.51 )
    681.3 ( 14.99 )
        Week 96 + 12 months: n= 606, 298
    707.6 ( 11.93 )
    676.2 ( 14.57 )
        Week 96 + 18 months: n= 459, 225
    713.3 ( 12.16 )
    686.1 ( 17.05 )
        Week 96 + 24 months: n= 278, 128
    712.7 ( 15.98 )
    686.4 ( 21.20 )
        Week 96 + 30 months: n= 134, 63
    730.4 ( 23.24 )
    685.8 ( 28.61 )
        Week 96 + 36 months: n= 52, 25
    732.0 ( 33.10 )
    733.3 ( 54.73 )
        Week 96 + 42 months: n= 16, 7
    714.3 ( 56.26 )
    705.6 ( 112.99 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Adherence of >95% From Week 96 to End of extension

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    End point title
    		 Percentage of Subjects with Treatment Adherence of >95% From Week 96 to End of extension [30]
    End point description
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability and was calculated cumulative from start of treatment/switch to last study drug intake by determination of the cumulative treatment adherence in subjects who returned all dispensed bottles prior to or at the last visit in the study from Week 96 to end of extension. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment. Here, N (number of subjects analyzed) indicates the number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 96 to end of extension (up to 42 months)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    363
    216
    Units: Percentage of subjects
        number (not applicable)
    89.5
    89.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing Grade 3 and 4 AEs, Serious Adverse Events (SAEs), and Premature Discontinuation due to AEs Post-Week 96 to end of Extension

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    End point title
    		 Percentage of Subjects Experiencing Grade 3 and 4 AEs, Serious Adverse Events (SAEs), and Premature Discontinuation due to AEs Post-Week 96 to end of Extension [31]
    End point description
    AE is any untoward medical occurrence in subjects who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events were symptoms causing inability to perform usual social & functional activities. Grade 4 (Life-threatening) events were symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize subject and/or may require medical or surgical intervention to prevent one of the outcomes listed above. ITT analysis set included all the subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From Week 96 to end of extension (up to 42 months)
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint was planned to be analyzed for specified arms only.
    End point values
    		 D/C/F/TAF (Test) (Baseline to End of Extension [EOE]) Switch to D/C/F/TAF
    Number of subjects analysed
    699
    337
    Units: percentage of subjects
    number (not applicable)
        Grade 3 AEs
    5.7
    5.0
        Grade 4 AEs
    2.1
    1.5
        SAEs
    7.3
    7.7
        Premature discontinuations due to AEs
    1.1
    2.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 65 months
    Adverse event reporting additional description
    The intent-to-treat (ITT) analysis set included all the subjects who were randomized and received at least one dose of study treatment in the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    D/C/F/TAF (Test)
    Reporting group description
    		 Subjects received a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily up to Week 48. After Week 48, all subjectss continued to receive D/C/F/TAF treatment (that is, initial switch to D/C/F/TAF group) up to Week 96. After Week 96, subjects were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available up to 42 months.

    Reporting group title
    Switch to D/C/F/TAF Group
    Reporting group description
    		 After Week 52, subjects earlier receiving treatment with bPI+F/TDF switched to D/C/F/TAF up to Week 96. After Week 96, sarticipants were given the opportunity to continue D/C/F/TAF treatment until D/C/F/TAF became commercially available for up to 42 months.

    Reporting group title
    Control
    Reporting group description
    		 Subjects received a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (F/TDF) up to Week 48.

    Serious adverse events
    		 D/C/F/TAF (Test) Switch to D/C/F/TAF Group Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    114 / 763 (14.94%)
    42 / 352 (11.93%)
    18 / 378 (4.76%)
         number of deaths (all causes)
    4
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal Squamous Cell Carcinoma
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anogenital Warts
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Enchondromatosis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hodgkin's Disease
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's Lymphoma
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Melanoma
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Neoplasm
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Stenosis
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 763 (0.26%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Stenosis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic Pregnancy
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain Death
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 763 (0.26%)
    2 / 352 (0.57%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical Failure
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Jarisch-Herxheimer Reaction
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Bereavement
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment Disorder
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 763 (0.13%)
    3 / 352 (0.85%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug Abuse
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Personality Disorder
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 763 (0.13%)
    3 / 352 (0.85%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device Breakage
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device Loosening
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase Increased
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biopsy Lymph Gland
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen Saturation Decreased
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    3 / 763 (0.39%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye Injury
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot Fracture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign Body in Gastrointestinal Tract
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament Injury
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Injury
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    3 / 763 (0.39%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative Ileus
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull Fracture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    4 / 763 (0.52%)
    1 / 352 (0.28%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid Artery Aneurysm
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid Artery Stenosis
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Essential Tremor
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 763 (0.39%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of Consciousness
         subjects affected / exposed
    2 / 763 (0.26%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Adhesions
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Inflammation
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus Hernia
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammatory Bowel Disease
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal Rupture
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic Ulcer
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Perforation
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis Acute
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    3 / 763 (0.39%)
    1 / 352 (0.28%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Mass
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Cushing's Syndrome
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seronegative Arthritis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess Limb
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess Oral
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 763 (0.26%)
    3 / 352 (0.85%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 763 (0.26%)
    2 / 352 (0.57%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon Gangrene
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea Infectious
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    4 / 763 (0.52%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fournier's Gangrene
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 763 (0.52%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Shigella
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin Abscess
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes Simplex Meningitis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphogranuloma Venereum
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perineal Abscess
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 763 (1.31%)
    3 / 352 (0.85%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Respiratory Syncytial Viral
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary Syphilis
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 763 (0.00%)
    2 / 352 (0.57%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 763 (0.13%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syphilis
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth Infection
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 763 (0.00%)
    0 / 352 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 763 (0.00%)
    1 / 352 (0.28%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic Hyperosmolar Nonketotic Syndrome
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    1 / 763 (0.13%)
    0 / 352 (0.00%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 D/C/F/TAF (Test) Switch to D/C/F/TAF Group Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    584 / 763 (76.54%)
    213 / 352 (60.51%)
    222 / 378 (58.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    47 / 763 (6.16%)
    11 / 352 (3.13%)
    7 / 378 (1.85%)
         occurrences all number
    50
    11
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    93 / 763 (12.19%)
    29 / 352 (8.24%)
    18 / 378 (4.76%)
         occurrences all number
    114
    32
    21
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    54 / 763 (7.08%)
    19 / 352 (5.40%)
    13 / 378 (3.44%)
         occurrences all number
    60
    19
    13
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    64 / 763 (8.39%)
    9 / 352 (2.56%)
    7 / 378 (1.85%)
         occurrences all number
    84
    10
    7
    Diarrhoea
         subjects affected / exposed
    104 / 763 (13.63%)
    40 / 352 (11.36%)
    18 / 378 (4.76%)
         occurrences all number
    138
    51
    21
    Nausea
         subjects affected / exposed
    41 / 763 (5.37%)
    12 / 352 (3.41%)
    8 / 378 (2.12%)
         occurrences all number
    49
    17
    9
    Vomiting
         subjects affected / exposed
    41 / 763 (5.37%)
    6 / 352 (1.70%)
    4 / 378 (1.06%)
         occurrences all number
    47
    7
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    75 / 763 (9.83%)
    21 / 352 (5.97%)
    17 / 378 (4.50%)
         occurrences all number
    94
    22
    17
    Oropharyngeal Pain
         subjects affected / exposed
    43 / 763 (5.64%)
    7 / 352 (1.99%)
    13 / 378 (3.44%)
         occurrences all number
    53
    9
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    43 / 763 (5.64%)
    12 / 352 (3.41%)
    6 / 378 (1.59%)
         occurrences all number
    45
    13
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    41 / 763 (5.37%)
    14 / 352 (3.98%)
    12 / 378 (3.17%)
         occurrences all number
    46
    17
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    84 / 763 (11.01%)
    22 / 352 (6.25%)
    9 / 378 (2.38%)
         occurrences all number
    104
    31
    10
    Back Pain
         subjects affected / exposed
    107 / 763 (14.02%)
    31 / 352 (8.81%)
    23 / 378 (6.08%)
         occurrences all number
    136
    36
    27
    Osteopenia
         subjects affected / exposed
    49 / 763 (6.42%)
    0 / 352 (0.00%)
    22 / 378 (5.82%)
         occurrences all number
    49
    0
    22
    Pain in Extremity
         subjects affected / exposed
    51 / 763 (6.68%)
    14 / 352 (3.98%)
    15 / 378 (3.97%)
         occurrences all number
    64
    16
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    73 / 763 (9.57%)
    21 / 352 (5.97%)
    10 / 378 (2.65%)
         occurrences all number
    95
    24
    10
    Gastroenteritis
         subjects affected / exposed
    44 / 763 (5.77%)
    15 / 352 (4.26%)
    12 / 378 (3.17%)
         occurrences all number
    49
    17
    14
    Influenza
         subjects affected / exposed
    53 / 763 (6.95%)
    10 / 352 (2.84%)
    7 / 378 (1.85%)
         occurrences all number
    60
    12
    8
    Nasopharyngitis
         subjects affected / exposed
    144 / 763 (18.87%)
    42 / 352 (11.93%)
    42 / 378 (11.11%)
         occurrences all number
    199
    54
    50
    Pharyngitis
         subjects affected / exposed
    58 / 763 (7.60%)
    14 / 352 (3.98%)
    11 / 378 (2.91%)
         occurrences all number
    79
    20
    11
    Sinusitis
         subjects affected / exposed
    52 / 763 (6.82%)
    13 / 352 (3.69%)
    12 / 378 (3.17%)
         occurrences all number
    65
    15
    12
    Syphilis
         subjects affected / exposed
    57 / 763 (7.47%)
    20 / 352 (5.68%)
    13 / 378 (3.44%)
         occurrences all number
    67
    22
    13
    Upper Respiratory Tract Infection
         subjects affected / exposed
    163 / 763 (21.36%)
    56 / 352 (15.91%)
    39 / 378 (10.32%)
         occurrences all number
    280
    84
    48
    Metabolism and nutrition disorders
    Vitamin D Deficiency
         subjects affected / exposed
    74 / 763 (9.70%)
    11 / 352 (3.13%)
    29 / 378 (7.67%)
         occurrences all number
    75
    11
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2014
    The overall reason for the Protocol Amendment-2 was the design of a separate efficacy study in treatment-naïve human immunodeficiency virus type 1 (HIV-1) infected subjects and a re-orientation of the present study into a 48-week safety study. The timing of virologic HIV-1 ribonucleic acid (RNA) retesting was also amended upon regulatory request.
    06 Mar 2015
    The overall reason for the Protocol Amendment-3 was the change of the primary endpoint into an efficacy endpoint.
    29 May 2015
    The overall reason for the Protocol Amendment-4 was the increase in sample size to approximately 1,100 subjects, in order to yield enough power with an expected rebound rate reassessed from 2 percent (%) to 4%.

    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.
    The limitation of the study was the open-label design.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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