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    Clinical Trial Results:
    A Phase 3 Open-label Safety Study of Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients with Mild to Moderate Renal Impairment

    Summary
    EudraCT number
    		 2011-000488-29
    Trial protocol
    		 GB   AT  
    Global end of trial date
    16 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2016
    First version publication date
    03 Mar 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-236-0118
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01363011
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is to characterize the effect of cobicistat-based regimens on parameters of renal function in participants with HIV infection and who have mild to moderate renal impairment, and to assess the safety and tolerability of the regimens in order to generate appropriate dosing recommendations.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United States: 52
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Dominican Republic: 6
    Country: Number of subjects enrolled
    Australia: 6
    Worldwide total number of subjects
    106
    EEA total number of subjects
    27
    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)
    93
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at a total of 40 study sites in Australia, Europe, and North America. The first participant was screened on 13 May 2011. The last study visit occurred on 16 February 2015.

    Pre-assignment
    Screening details
    		 177 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 E/C/F/TDF (Cohort 1)
    Arm description
    		 Main Study: Participants who had not received prior antiretroviral (ARV) treatment and who were virologically unsuppressed at baseline initiated treatment with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild®; E/C/F/TDF) single-tablet regimen (STR) once daily for up to 96 weeks. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.
    Arm type
    		 Experimental

    Investigational medicinal product name
    E/C/F/TDF
    Investigational medicinal product code
    Other name
    Stribild®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) (150/150/200/300 mg) single-tablet regimen (STR) administered orally once daily

    Arm title
    		 COBI+PI+2 NRTIs (Cohort 2)
    Arm description
    		 Main Study: Participants who had received prior ARV treatment and who were virologically suppressed at baseline switched their regimen's pharmacoenhancer component from ritonavir to cobicistat (Tybost®; COBI), while continuing the other components of their ARV regimen (atazanavir (ATV) or darunavir (DRV) plus 2 nucleoside reverse transcriptase inhibitors (NRTI)) for up to 96 weeks. These 2 NRTIs may have included abacavir (ABC), lamivudine (3TC)/zidovudine (ZDV), didanosine (DDI), emtricitabine (FTC), ABC/3TC, 3TC, tenofovir disoproxil fumarate (TDF), or emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF), administered according to prescribing information. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobicistat
    Investigational medicinal product code
    Other name
    Tybost®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobicistat (COBI) 150 mg tablet administered with food orally once daily

    Investigational medicinal product name
    Atazanavir
    Investigational medicinal product code
    Other name
    Reyataz®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atazanavir (ATV) 300 mg tablet administered orally once daily

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    Other name
    Prezista®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Darunavir (DRV) 800 mg tablet administered orally once daily

    Investigational medicinal product name
    Nucleoside reverse transcriptase inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 investigator-selected nucleoside reverse transcriptase inhibitors (NRTI), which may have included ABC, 3TC/ZDV, DDI, FTC, ABC/3TC, 3TC, TDF, or FTC/TDF, administered according to prescribing information.

    Number of subjects in period 1
    		E/C/F/TDF (Cohort 1) COBI+PI+2 NRTIs (Cohort 2)
    Started
    33
    73
    Completed
    29
    64
    Not completed
    4
    9
         Withdrew Consent
    1
    4
         Adverse event, non-fatal
    2
    3
         Investigator's Discretion
    1
    1
         Protocol Violation
    -
    1
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 E/C/F/TDF (Cohort 1)
    Arm description
    		 Main Study: Participants who had not received prior ARV treatment and who were virologically unsuppressed at baseline initiated treatment with E/C/F/TDF STR once daily for up to 96 weeks. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.
    Arm type
    		 Experimental

    Investigational medicinal product name
    E/C/F/TDF
    Investigational medicinal product code
    Other name
    Stribild®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    E/C/F/TDF (150/150/200/300 mg) STR administered orally once daily

    Arm title
    		 COBI+PI+2 NRTIs (Cohort 2)
    Arm description
    		 Main Study: Participants who had received prior ARV treatment and who were virologically suppressed at baseline switched their regimen's pharmacoenhancer component from ritonavir to COBI, while continuing the other components of their ARV regimen (ATV or DRV plus 2 NRTIs) for up to 96 weeks. These 2 NRTIs may have included ABC, 3TC/ZDV, DDI, FTC, ABC/3TC, 3TC, TDF, or FTC/TDF, administered according to prescribing information. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobicistat
    Investigational medicinal product code
    Other name
    Tybost®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    COBI 150 mg tablet administered with food orally once daily

    Investigational medicinal product name
    Atazanavir
    Investigational medicinal product code
    Other name
    Reyataz®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ATV 300 mg tablet administered orally once daily

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    Other name
    Prezista®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DRV 800 mg tablet administered orally once daily

    Investigational medicinal product name
    Nucleoside reverse transcriptase inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 investigator-selected NRTIs, which may have included ABC, 3TC/ZDV, DDI, FTC, ABC/3TC, 3TC, TDF, or FTC/TDF, administered according to prescribing information.

    Number of subjects in period 2 [1]
    		E/C/F/TDF (Cohort 1) COBI+PI+2 NRTIs (Cohort 2)
    Started
    18
    49
    Completed
    13
    41
    Not completed
    5
    8
         Withdrew Consent
    -
    1
         Rolled Over to Another Gilead Study
    2
    1
         Adverse event, non-fatal
    1
    1
         Investigator's Discretion
    2
    2
         Lost to follow-up
    -
    2
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: For Cohort 1, 11 participants who completed the main study did not enroll into the extension phase. For Cohort 2, 15 participants who completed the main study did not enroll into the extension phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    E/C/F/TDF (Cohort 1)
    Reporting group description
    		 Main Study: Participants who had not received prior antiretroviral (ARV) treatment and who were virologically unsuppressed at baseline initiated treatment with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild®; E/C/F/TDF) single-tablet regimen (STR) once daily for up to 96 weeks. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.

    Reporting group title
    COBI+PI+2 NRTIs (Cohort 2)
    Reporting group description
    		 Main Study: Participants who had received prior ARV treatment and who were virologically suppressed at baseline switched their regimen's pharmacoenhancer component from ritonavir to cobicistat (Tybost®; COBI), while continuing the other components of their ARV regimen (atazanavir (ATV) or darunavir (DRV) plus 2 nucleoside reverse transcriptase inhibitors (NRTI)) for up to 96 weeks. These 2 NRTIs may have included abacavir (ABC), lamivudine (3TC)/zidovudine (ZDV), didanosine (DDI), emtricitabine (FTC), ABC/3TC, 3TC, tenofovir disoproxil fumarate (TDF), or emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF), administered according to prescribing information. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.

    Reporting group values
    		 E/C/F/TDF (Cohort 1) COBI+PI+2 NRTIs (Cohort 2) Total
    Number of subjects
    		 33 73 106
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50 ± 12.1 54 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    		 6 13 19
        Male
    		 27 60 87
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 0 1 1
        Black or African Heritage
    		 13 14 27
        White
    		 14 56 70
        Other
    		 5 2 7
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 9 19 28
        Non-Hispanic/Latino
    		 24 54 78
    HIV Disease Status
    Units: Subjects
        Asymptomatic
    		 28 37 65
        Symptomatic HIV Infection
    		 3 18 21
        AIDS
    		 2 18 20
    Hepatitis B Virus (HBV) Surface Antigen Status
    Units: Subjects
        Positive
    		 1 4 5
        Negative
    		 32 69 101
    Hepatitis C Virus (HCV) Antibody Status
    Units: Subjects
        Positive
    		 2 10 12
        Negative
    		 30 63 93
        Indeterminate
    		 1 0 1
    HIV-1 RNA Category
    Units: Subjects
        < 50 copies/mL
    		 0 73 73
        ≥ 50 to < 1,000 copies/mL
    		 0 0 0
        ≥ 1,000 to ≤ 100,000 copies/ mL
    		 24 0 24
        > 100,000 copies/mL
    		 9 0 9
    CD4 Cell Count
    Units: Subjects
        ≤ 50 cells/μL
    		 1 0 1
        51 to ≤ 200 cells/μL
    		 3 3 6
        201 to ≤ 350 cells/μL
    		 13 5 18
        351 to ≤ 500 cells/μL
    		 10 16 26
        > 500 cells/μL
    		 6 49 55

    End points

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    End points reporting groups
    Reporting group title
    E/C/F/TDF (Cohort 1)
    Reporting group description
    		 Main Study: Participants who had not received prior antiretroviral (ARV) treatment and who were virologically unsuppressed at baseline initiated treatment with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild®; E/C/F/TDF) single-tablet regimen (STR) once daily for up to 96 weeks. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.

    Reporting group title
    COBI+PI+2 NRTIs (Cohort 2)
    Reporting group description
    		 Main Study: Participants who had received prior ARV treatment and who were virologically suppressed at baseline switched their regimen's pharmacoenhancer component from ritonavir to cobicistat (Tybost®; COBI), while continuing the other components of their ARV regimen (atazanavir (ATV) or darunavir (DRV) plus 2 nucleoside reverse transcriptase inhibitors (NRTI)) for up to 96 weeks. These 2 NRTIs may have included abacavir (ABC), lamivudine (3TC)/zidovudine (ZDV), didanosine (DDI), emtricitabine (FTC), ABC/3TC, 3TC, tenofovir disoproxil fumarate (TDF), or emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF), administered according to prescribing information. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.
    Reporting group title
    E/C/F/TDF (Cohort 1)
    Reporting group description
    		 Main Study: Participants who had not received prior ARV treatment and who were virologically unsuppressed at baseline initiated treatment with E/C/F/TDF STR once daily for up to 96 weeks. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.

    Reporting group title
    COBI+PI+2 NRTIs (Cohort 2)
    Reporting group description
    		 Main Study: Participants who had received prior ARV treatment and who were virologically suppressed at baseline switched their regimen's pharmacoenhancer component from ritonavir to COBI, while continuing the other components of their ARV regimen (ATV or DRV plus 2 NRTIs) for up to 96 weeks. These 2 NRTIs may have included ABC, 3TC/ZDV, DDI, FTC, ABC/3TC, 3TC, TDF, or FTC/TDF, administered according to prescribing information. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.

    Primary: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) Using the Cockcroft-Gault (CG) Equation at Week 24 (Cohort 1)

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    End point title
    		 Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) Using the Cockcroft-Gault (CG) Equation at Week 24 (Cohort 1) [1] [2]
    End point description
    Change from baseline in eGFR-CG equation at Week 24 was analyzed in Cohort 1 (treatment-naive).
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 33)
    72.9 (64.7 to 81.1)
        Change at Week 24 (n = 30)
    -5.2 (-13.2 to 1)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR-CG at Week 24 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-CG at Week 24 (Cohort 2) [3] [4]
    End point description
    Change from baseline in eGFR-CG equation at Week 24 was analyzed in Cohort 2 (treatment-experienced).
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 73)
    71.4 (61.9 to 80.7)
        Change at Week 24 (n = 67)
    -3.7 (-7.4 to 2)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR Using the Modification of Diet in Renal (MDRD) Equation at Week 24 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR Using the Modification of Diet in Renal (MDRD) Equation at Week 24 (Cohort 1) [5] [6]
    End point description
    Change from baseline in eGFR-MDRD equation at Week 24 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 33)
    77.1 (64.3 to 87.2)
        Change at Week 24 (n = 30)
    -7.4 (-16.3 to -1.2)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR-MDRD at Week 24 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-MDRD at Week 24 (Cohort 2) [7] [8]
    End point description
    Change from baseline in eGFR-MDRD equation at Week 24 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 73)
    65.8 (56.2 to 75.2)
        Change at Week 24 (n = 67)
    -3.4 (-7.5 to 1.9)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR Using the Chronic Kidney Disease, Epidemiology Collaboration (CKD-EPI) Formula Based on Cystatin C Equation at Week 24 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR Using the Chronic Kidney Disease, Epidemiology Collaboration (CKD-EPI) Formula Based on Cystatin C Equation at Week 24 (Cohort 1) [9] [10]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 33)
    77.6 (61.7 to 90.5)
        Change at Week 24 (n = 30)
    0.3 (-3.3 to 6.1)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Formula Based on Cystatin C Equation at Week 24 (Cohort 2) [11] [12]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 73)
    78.6 (67 to 94.4)
        Change at Week 24 (n = 67)
    -2.7 (-6.8 to 1.9)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 1) [13] [14]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 33)
    76.9 (61.7 to 90.1)
        Change at Week 24 (n = 30)
    0.3 (-3.7 to 5.7)
    No statistical analyses for this end point

    Primary: Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation, Adjusted at Week 24 (Cohort 2) [15] [16]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Week 24 was analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Baseline (n = 73)
    78.2 (67.1 to 92.4)
        Change at Week 24 (n = 67)
    -2.8 (-6.7 to 1.9)
    No statistical analyses for this end point

    Primary: Change From Baseline in Actual Glomerular Filtration Rate (aGFR) at Weeks 2, 4, and 24 (Cohort 1)

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    End point title
    		 Change From Baseline in Actual Glomerular Filtration Rate (aGFR) at Weeks 2, 4, and 24 (Cohort 1) [17] [18]
    End point description
    Change from baseline in aGFR at Weeks 2, 4, and 24 was analyzed in Cohort 1 (treatment-naive). aGFR was calculated using iohexol plasma clearance. Pharmacokinetic/Pharmacodynamic (PK/PD) Substudy Analysis Set (treatment-naive only): participants in the treatment-naive group who were enrolled and received at least one dose of study drug and who had data for steady-state PK parameters at the relevant time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Weeks 2, 4, and 24
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    1
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Baseline
    81.6 (81.6 to 81.6)
        Change at Week 2
    -12.1 (-12.1 to -12.1)
        Change at Week 4
    -7.3 (-7.3 to -7.3)
        Change at Week 24
    -3.3 (-3.3 to -3.3)
    No statistical analyses for this end point

    Primary: Change From Baseline in aGFR at Weeks 2, 4, and 24 (Cohort 2)

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    End point title
    		 Change From Baseline in aGFR at Weeks 2, 4, and 24 (Cohort 2) [19] [20]
    End point description
    Change from baseline in aGFR at Weeks 2, 4, and 24 was analyzed in Cohort 2 (treatment-experienced). aGFR was calculated using iohexol plasma clearance. PK/PD Substudy Analysis Set (treatment-experienced only): participants in the treatment-experienced group who were enrolled and received at least one dose of study drug and who had data for steady-state PK parameters at the relevant time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Weeks 2, 4, and 24
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    14
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Baseline
    82.5 (55.3 to 112.9)
        Change at Week 2 (n=13)
    1.6 (-12.3 to 9.2)
        Change at Week 4 (n=13)
    7 (-14.6 to 14.6)
        Change at Week 24 (n=11)
    -4.1 (-13.5 to 13.2)
    No statistical analyses for this end point

    Primary: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 1)

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    End point title
    		 Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 1) [21] [22]
    End point description
    The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed in Cohort 1 (treatment-naive) using the FDA snapshot analysis algorithm.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: percentage of participants
        number (not applicable)
    84.8
    No statistical analyses for this end point

    Primary: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 2)

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    End point title
    		 Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 (Cohort 2) [23] [24]
    End point description
    The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed in Cohort 2 (treatment-experienced) using the FDA snapshot analysis algorithm.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed.
    [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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: percentage of participants
        number (not applicable)
    90.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 1) [25]
    End point description
    Change from baseline in eGFR-CG at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 28)
    -7.6 (-12.2 to -2.2)
        Change at Week 96 (n = 25)
    -7.9 (-14.2 to -4.1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-CG at Weeks 48 and 96 (Cohort 2) [26]
    End point description
    Change from baseline in eGFR-CG at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 63)
    -3.8 (-9 to 0.8)
        Change at Week 96 (n = 50)
    -5 (-13 to 0.1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 1) [27]
    End point description
    Change from baseline in eGFR-MDRD at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 28)
    -12.1 (-17.6 to -6.5)
        Change at Week 96 (n = 25)
    -12.9 (-17.7 to -5.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-MDRD at Weeks 48 and 96 (Cohort 2) [28]
    End point description
    Change from baseline in eGFR-MDRD at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 63)
    -3.9 (-8.1 to 1.4)
        Change at Week 96 (n = 50)
    -2.8 (-13.7 to 2.2)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 1) [29]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 28)
    1.9 (-7.1 to 6.9)
        Change at Week 96 (n = 25)
    12.4 (-0.6 to 20.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation at Weeks 48 and 96 (Cohort 2) [30]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (not adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 63)
    -4.7 (-12 to 4.3)
        Change at Week 96 (n = 50)
    -2.4 (-7.3 to 9.4)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 1)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 1) [31]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive). The calculation was normalized to 1.73 m^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 28)
    1.6 (-8 to 6.9)
        Change at Week 96 (n = 25)
    12.6 (-0.9 to 19.2)
    No statistical analyses for this end point

    Secondary: Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 2)

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    End point title
    		 Change From Baseline in eGFR-CKD-EPI Based on Cystatin C Equation (Adjusted) at Weeks 48 and 96 (Cohort 2) [32]
    End point description
    Change from baseline in eGFR-CKD-EPI based on cystatin C equation (adjusted for age, sex, and race) at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced). The calculation was normalized to 1.73 m^2 body surface area. This outcome is to measure the long-term effect of COBI-containing regimens on renal parameters.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48 and 96
    Notes
    [32] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: mL/min/1.73 m^2
    median (inter-quartile range (Q1-Q3))
        Change at Week 48 (n = 63)
    -4.7 (-11.7 to 3.9)
        Change at Week 96 (n = 50)
    -2.8 (-7.4 to 8.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 1)

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    End point title
    		 Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 1) [33]
    End point description
    The percentage of participants with HIV-1 RNA < 50 copies/mL at Weeks 48 and 96 were analyzed in Cohort 1 (treatment-naive) using the FDA snapshot analysis algorithm.
    End point type
    Secondary
    End point timeframe
    Weeks 48 and 96
    Notes
    [33] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: percentage of participants
    number (not applicable)
        Week 48 (n = 33)
    78.8
        Week 96 (n = 27)
    88.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 2)

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    End point title
    		 Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 (Cohort 2) [34]
    End point description
    The percentage of participants with HIV-1 RNA < 50 copies/mL at Weeks 48 and 96 were analyzed in Cohort 2 (treatment-experienced) using the FDA snapshot analysis algorithm.
    End point type
    Secondary
    End point timeframe
    Weeks 48 and 96
    Notes
    [34] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: percentage of participants
    number (not applicable)
        Week 48 (n = 73)
    82.2
        Week 96 (n = 54)
    90.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Adverse Events (Cohort 1)

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    End point title
    		 Percentage of Participants Who Experienced Adverse Events (Cohort 1) [35]
    End point description
    Adverse events (AEs) occurring from baseline up to 30 days following the last dose of study drug were summarized for Cohort 1 (treatment-naive). A participant was counted once if they had a qualifying event.
    End point type
    Secondary
    End point timeframe
    Up to 147 weeks plus 30 days
    Notes
    [35] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: percentage of participants
    number (not applicable)
        Any AE
    100
        Drug-related AE
    48.5
        Grade 3 or higher AE
    21.2
        AE leading to drug discontinuation
    12.1
        Serious AE
    18.2
        AE of proximal renal tubulopathy
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Adverse Events (Cohort 2)

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    End point title
    		 Percentage of Participants Who Experienced Adverse Events (Cohort 2) [36]
    End point description
    Adverse events (AEs) occurring from baseline up to 30 days following the last dose of study drug were summarized for Cohort 2 (treatment-experienced). A participant was counted once if they had a qualifying event.
    End point type
    Secondary
    End point timeframe
    Up to 166 weeks plus 30 days
    Notes
    [36] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    73
    Units: percentage of participants
    number (not applicable)
        Any AE
    93.2
        Drug-related AE
    27.4
        Grade 3 or higher AE
    28.8
        AE leading to drug discontinuation
    11
        Serious AE
    15.1
        AE of proximal renal tubulopathy
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 1)

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    End point title
    		 Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 1) [37]
    End point description
    Laboratory abnormalities were summarized for Cohort 1 (treatment-naive) and were defined as values that increased at least one toxicity grade from baseline at any time postbaseline up to and including the date of last dose of study drug plus 30 days. A participant was counted once if they had a qualifying event.
    End point type
    Secondary
    End point timeframe
    Up to 147 weeks plus 30 days
    Notes
    [37] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    33
    Units: percentage of participants
    number (not applicable)
        Any laboratory abnormality
    100
        Grade 3 or 4 laboratory abnormality
    39.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 2)

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    End point title
    		 Percentage of Participants Who Experienced Graded Laboratory Abnormalities (Cohort 2) [38]
    End point description
    Laboratory abnormalities were summarized for Cohort 2 (treatment-experienced) and were defined as values that increased at least one toxicity grade from baseline at any time postbaseline up to and including the date of last dose of study drug plus 30 days. A participant was counted once if they had a qualifying event.
    End point type
    Secondary
    End point timeframe
    Up to 166 weeks plus 30 days
    Notes
    [38] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    72 [39]
    Units: percentage of participants
    number (not applicable)
        Any laboratory abnormality
    100
        Grade 3 or 4 laboratory abnormality
    50
    Notes
    [39] - Participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: AUCtau (Cohort 1)

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    End point title
    		 Plasma Pharmacokinetics of COBI: AUCtau (Cohort 1) [40]
    End point description
    AUCtau was analyzed for Cohort 1 (treatment-naive) and was defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Data presented are the mean values; standard deviation is not applicable because only 1 participant was analyzed.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [40] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    1 [41]
    Units: mean (h*ng/mL)
    number (not applicable)
        Week 2
    16554.7
        Week 4
    12704.1
        Week 24
    9799.7
    Notes
    [41] - PK/PD Substudy Analysis Set (treatment-naive only)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: AUCtau (Cohort 2)

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    End point title
    		 Plasma Pharmacokinetics of COBI: AUCtau (Cohort 2) [42]
    End point description
    AUCtau was analyzed for Cohort 2 (treatment-experienced) and was defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [42] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    14 [43]
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Week 2 (n = 13)
    12458 ± 6179.06
        Week 4 (n = 13)
    11165.3 ± 4185.86
        Week 24 (n = 11)
    13980.5 ± 8029.03
    Notes
    [43] - Participants in the PK/PD Substudy Analysis Set with available postbaseline data were analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: Cmax (Cohort 1)

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    End point title
    		 Plasma Pharmacokinetics of COBI: Cmax (Cohort 1) [44]
    End point description
    Cmax was analyzed for Cohort 1 (treatment-naive) and was defined as the maximum observed concentration of drug in plasma. Data presented are the mean values; standard deviation is not applicable because only 1 participant was analyzed.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [44] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    1 [45]
    Units: mean (ng/mL)
    number (not applicable)
        Week 2
    1734.6
        Week 4
    1522.9
        Week 24
    1266.4
    Notes
    [45] - PK/PD Substudy Analysis Set (treatment-naive only)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: Cmax (Cohort 2)

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    End point title
    		 Plasma Pharmacokinetics of COBI: Cmax (Cohort 2) [46]
    End point description
    Cmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the maximum observed concentration of drug in plasma.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [46] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    14 [47]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 2 (n = 13)
    1366.7 ± 508.32
        Week 4 (n = 13)
    1297.7 ± 424.06
        Week 24 (n = 11)
    1586.6 ± 618.84
    Notes
    [47] - Participants in the PK/PD Substudy Analysis Set with available postbaseline data were analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: Ctau (Cohort 1)

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    End point title
    		 Plasma Pharmacokinetics of COBI: Ctau (Cohort 1) [48]
    End point description
    Ctau was analyzed for Cohort 1 (treatment-naive) and was defined as the observed drug concentration at the end of the dosing interval. Mean values are reported; standard deviation is not applicable because only 1 participant was analyzed.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [48] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    1 [49]
    Units: ng/mL
    number (not applicable)
        Week 2
    150.5
        Week 4
    37.3
        Week 24
    24.2
    Notes
    [49] - PK/PD Substudy Analysis Set (treatment-naive only)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: Ctau (Cohort 2)

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    End point title
    		 Plasma Pharmacokinetics of COBI: Ctau (Cohort 2) [50]
    End point description
    Ctau was analyzed for Cohort 2 (treatment-experienced) and was defined as the observed drug concentration at the end of the dosing interval.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [50] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    14 [51]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 2 (n = 13)
    79.9 ± 79.01
        Week 4 (n = 13)
    71.3 ± 61.27
        Week 24 (n = 11)
    139.8 ± 238.84
    Notes
    [51] - Participants in the PK/PD Substudy Analysis Set with available postbaseline data were analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: Tmax (Cohort 1)

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    End point title
    		 Plasma Pharmacokinetics of COBI: Tmax (Cohort 1) [52]
    End point description
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    End point type
    Secondary
    End point timeframe
    Tmax was analyzed for Cohort 1 (treatment-naive) and was defined as the time of Cmax.
    Notes
    [52] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    1 [53]
    Units: hours
    median (inter-quartile range (Q1-Q3))
        Week 2
    4 (4 to 4)
        Week 4
    2 (2 to 2)
        Week 24
    4 (4 to 4)
    Notes
    [53] - PK/PD Substudy Analysis Set (treatment-naive only)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: Tmax (Cohort 2)

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    End point title
    		 Plasma Pharmacokinetics of COBI: Tmax (Cohort 2) [54]
    End point description
    Tmax was analyzed for Cohort 2 (treatment-experienced) and was defined as the time of Cmax.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [54] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    14 [55]
    Units: hours
    median (inter-quartile range (Q1-Q3))
        Week 2 (n = 13)
    3.92 (3 to 4.92)
        Week 4 (n = 13)
    4.92 (3.02 to 5)
        Week 24 (n = 11)
    3 (2 to 4.05)
    Notes
    [55] - Participants in the PK/PD Substudy Analysis Set with available postbaseline data were analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: t1/2 (Cohort 1)

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    End point title
    		 Plasma Pharmacokinetics of COBI: t1/2 (Cohort 1) [56]
    End point description
    t1/2 was analyzed for Cohort 1 (treatment-naive) and was defined as the estimate of the terminal elimination half-life of the drug.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [56] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 E/C/F/TDF (Cohort 1)
    Number of subjects analysed
    1 [57]
    Units: hours
    median (inter-quartile range (Q1-Q3))
        Week 2
    6.14 (6.14 to 6.14)
        Week 4
    3.57 (3.57 to 3.57)
        Week 24
    3.63 (3.63 to 3.63)
    Notes
    [57] - PK/PD Substudy Analysis Set (treatment-naive only)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics of COBI: t1/2 (Cohort 2)

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    End point title
    		 Plasma Pharmacokinetics of COBI: t1/2 (Cohort 2) [58]
    End point description
    t1/2 was analyzed for Cohort 2 (treatment-experienced) and was defined as the estimate of the terminal elimination half-life of the drug.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at 0 (predose), 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 8.0, 12.0, and 24.0 hours postdose at baseline and Weeks 2, 4, and 24.
    Notes
    [58] - 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: Data are being presented as separate endpoints for each Cohort because the differing populations groups are not comparable.
    End point values
    		 COBI+PI+2 NRTIs (Cohort 2)
    Number of subjects analysed
    14 [59]
    Units: hours
    median (inter-quartile range (Q1-Q3))
        Week 2 (n = 13)
    4.37 (3.63 to 4.91)
        Week 4 (n = 12)
    3.98 (3.53 to 4.34)
        Week 24 (n = 10)
    3.77 (3.46 to 3.95)
    Notes
    [59] - Participants in the PK/PD Substudy Analysis Set with available postbaseline data were analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of study drug treatment (average: Cohort 1 = 93.7 weeks; Cohort 2 = 101.2 weeks) plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set: participants were randomized and received at least one dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    E/C/F/TDF (Cohort 1)
    Reporting group description
    		 Main Study: Participants who had not received prior ARV treatment and who were virologically unsuppressed at baseline initiated treatment with E/C/F/TDF STR once daily for up to 96 weeks. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of E/C/F/TDF was received in the applicable country.

    Reporting group title
    COBI+PI+2 NRTIs (Cohort 2)
    Reporting group description
    		 Main Study: Participants who had received prior ARV treatment and who were virologically suppressed at baseline switched their regimen's pharmacoenhancer component from ritonavir to COBI, while continuing the other components of their ARV regimen (ATV or DRV plus 2 NRTIs) for up to 96 weeks. These 2 NRTIs may have included ABC, 3TC/ZDV, DDI, FTC, ABC/3TC, 3TC, TDF, or FTC/TDF, administered according to prescribing information. Extension Phase: Participants continued their treatment until all participants discontinued from the study or commercial approval of cobicistat was received in the applicable country.

    Serious adverse events
    		 E/C/F/TDF (Cohort 1) COBI+PI+2 NRTIs (Cohort 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 33 (18.18%)
    11 / 73 (15.07%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hodgkin's disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Skull fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal fistula
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 E/C/F/TDF (Cohort 1) COBI+PI+2 NRTIs (Cohort 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    67 / 73 (91.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 73 (6.85%)
         occurrences all number
    2
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 73 (6.85%)
         occurrences all number
    3
    5
    Oedema peripheral
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 73 (6.85%)
         occurrences all number
    4
    5
    Pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    3
    2
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 73 (10.96%)
         occurrences all number
    4
    8
    Oropharyngeal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    4
    2
    Hiccups
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 33 (21.21%)
    6 / 73 (8.22%)
         occurrences all number
    8
    7
    Abnormal dreams
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 73 (5.48%)
         occurrences all number
    1
    4
    Depression
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 73 (4.11%)
         occurrences all number
    2
    3
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    3
    2
    Glomerular filtration rate decreased
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    3
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 33 (18.18%)
    10 / 73 (13.70%)
         occurrences all number
    7
    11
    Dizziness
         subjects affected / exposed
    3 / 33 (9.09%)
    7 / 73 (9.59%)
         occurrences all number
    7
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 73 (1.37%)
         occurrences all number
    4
    1
    Lymphadenectomy
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    2
    3
    Neutropenia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 73 (1.37%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 33 (36.36%)
    10 / 73 (13.70%)
         occurrences all number
    16
    14
    Nausea
         subjects affected / exposed
    6 / 33 (18.18%)
    9 / 73 (12.33%)
         occurrences all number
    7
    10
    Vomiting
         subjects affected / exposed
    5 / 33 (15.15%)
    4 / 73 (5.48%)
         occurrences all number
    7
    4
    Constipation
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 73 (6.85%)
         occurrences all number
    4
    5
    Abdominal pain upper
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 73 (5.48%)
         occurrences all number
    2
    4
    Dyspepsia
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 73 (4.11%)
         occurrences all number
    3
    3
    Abdominal pain
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 73 (1.37%)
         occurrences all number
    3
    1
    Proctalgia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    8 / 73 (10.96%)
         occurrences all number
    0
    17
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 73 (10.96%)
         occurrences all number
    3
    9
    Skin lesion
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 73 (6.85%)
         occurrences all number
    0
    6
    Actinic keratosis
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    6
    Pruritus
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    2
    1
    Acne
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Dry skin
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 33 (3.03%)
    6 / 73 (8.22%)
         occurrences all number
    1
    9
    Nephrolithiasis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    2
    2
    Renal cyst
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 33 (6.06%)
    9 / 73 (12.33%)
         occurrences all number
    3
    9
    Back pain
         subjects affected / exposed
    5 / 33 (15.15%)
    5 / 73 (6.85%)
         occurrences all number
    5
    8
    Myalgia
         subjects affected / exposed
    3 / 33 (9.09%)
    6 / 73 (8.22%)
         occurrences all number
    3
    6
    Pain in extremity
         subjects affected / exposed
    4 / 33 (12.12%)
    4 / 73 (5.48%)
         occurrences all number
    4
    5
    Muscle spasms
         subjects affected / exposed
    1 / 33 (3.03%)
    5 / 73 (6.85%)
         occurrences all number
    2
    5
    Musculoskeletal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    5 / 73 (6.85%)
         occurrences all number
    1
    6
    Osteoporosis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    2
    2
    Osteopenia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 33 (18.18%)
    14 / 73 (19.18%)
         occurrences all number
    15
    22
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    15 / 73 (20.55%)
         occurrences all number
    2
    20
    Bronchitis
         subjects affected / exposed
    3 / 33 (9.09%)
    10 / 73 (13.70%)
         occurrences all number
    4
    14
    Influenza
         subjects affected / exposed
    4 / 33 (12.12%)
    8 / 73 (10.96%)
         occurrences all number
    4
    9
    Sinusitis
         subjects affected / exposed
    4 / 33 (12.12%)
    7 / 73 (9.59%)
         occurrences all number
    6
    7
    Urinary tract infection
         subjects affected / exposed
    5 / 33 (15.15%)
    3 / 73 (4.11%)
         occurrences all number
    5
    10
    Folliculitis
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 73 (6.85%)
         occurrences all number
    2
    6
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    5 / 73 (6.85%)
         occurrences all number
    1
    10
    Rhinitis
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 73 (5.48%)
         occurrences all number
    2
    7
    Acute sinusitis
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 73 (5.48%)
         occurrences all number
    1
    6
    Syphilis
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 73 (1.37%)
         occurrences all number
    4
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    4
    Gastroenteritis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    2
    2
    Oral candidiasis
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 73 (1.37%)
         occurrences all number
    4
    1
    Pyuria
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 73 (1.37%)
         occurrences all number
    3
    2
    Chikungunya virus infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    2
    1
    Herpes simplex
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    2
    1
    Tinea pedis
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    2
    1
    Urethritis
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    3
    1
    Tinea cruris
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 73 (6.85%)
         occurrences all number
    4
    5
    Hypokalaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 73 (5.48%)
         occurrences all number
    1
    4
    Gout
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    2
    4
    Hyperglycaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 73 (2.74%)
         occurrences all number
    5
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    5
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 73 (1.37%)
         occurrences all number
    2
    1
    Dehydration
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Hyperlipidaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2011
    Changed inclusion and exclusion criteria based on FDA Guidance for Industry “Pharmacokinetics in Patients with Impaired Renal Function,” and revised PK/PD substudy blood sampling procedures.
    26 Apr 2013
    Changed the study duration from 48 weeks to 96 weeks.

    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.
    There were no limitations affecting the analysis or results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25397568
    http://www.ncbi.nlm.nih.gov/pubmed/25469527
    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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