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    Clinical Trial Results:
    A Phase IIb Randomized, Controlled, Partially-Blinded Trial to Investigate Safety, Efficacy and Dose-response of BMS-663068/GSK3684934 in Treatment-experienced HIV-1 Subjects, Followed by an Open-label Period on the Recommended Dose

    Summary
    EudraCT number
    		 2011-000437-36
    Trial protocol
    		 DE   ES  
    Global end of trial date
    12 May 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Nov 2018
    First version publication date
    02 Sep 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    205889
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Other Identifier: Bristol-Myers Squibb: AI438-011
    Sponsors
    Sponsor organisation name
    ViiV Healthcare
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    17 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of four doses of fostemsavir by determining the proportion of participants with plasma Human Immunodeficiency Virus (HIV-1) Ribonucleic acid (RNA) < 50 copies per milliliter (c/mL) at Week 24. To assess the safety of four doses of fostemsavir in treatment-experienced HIV-1-infected participants through Week 24 by measuring frequency of Serious Adverse events (SAEs), and AEs leading to discontinuations.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 Participants in the fostemsavir groups and the ritonavir boosted atazanavir reference group received open-label background therapy of 400 mg RAL BID and 300 mg TDF QD
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jul 2011
    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
    Argentina: 18
    Country: Number of subjects enrolled
    Colombia: 12
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Mexico: 26
    Country: Number of subjects enrolled
    Peru: 51
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    South Africa: 66
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    254
    EEA total number of subjects
    18
    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)
    250
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with Human Immunodeficiency Virus (HIV-1) were randomized in ratio of 1:1:1:1:1 to 5 treatment arms of the study. Four groups with distinct dose of Fostemsavir (FTR, also referred BMS-663068) with Raltegravir (RAL) Tenofovir Disoproxil Fumarate (TDF). There was a reference group with ritonavir (r) boosted atazanavir (ATV), RAL and TDF.

    Pre-assignment
    Screening details
    		 A total of 581 participants were screened, 254 were enrolled of which 2 participants withdrew consent and 1 was randomized in error. A total 251 participants were randomized and treated of which 32 were in Monotherapy sub-study (only FTR) and continued to Primary study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    This was a partially-blinded study. All subjects and investigators were partially blinded to the dose of FTR until the last subject completed the Week 48 study visit procedures and an analysis of the Week 24 efficacy and safety data was conducted in order to determine the continuation dose, thereafter all subjects were switched to a continuation dose of FTR (1200 mg once daily), marking the end of the blinded phase of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FTR 400 mg BID/RAL/TDF
    Arm description
    		 Participants were randomized and administered 400 milligrams (mg) of FTR twice daily (BID) (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF once daily (QD) (open label).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomized to receive oral tablets of 400 and 800 twice daily and 600 and 1200 mg fostemsavir once daily for at least 96 weeks

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 400 mg raltegravir twice daily for at least 96 weeks

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 300 mg tenofovir once daily for at least 96 weeks

    Arm title
    		 FTR 800 mg BID/RAL/TDF
    Arm description
    		 Participants were randomized and administered 800 mg of FTR BID (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomized to receive oral tablets of 400 and 800 twice daily and 600 and 1200 mg fostemsavir once daily for at least 96 weeks

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 300 mg tenofovir once daily for at least 96 weeks

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 400 mg raltegravir twice daily for at least 96 weeks

    Arm title
    		 FTR 600 mg QD/RAL/TDF
    Arm description
    		 Participants were randomized and administered 600 mg of FTR QD (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomized to receive oral tablets of 400 and 800 twice daily and 600 and 1200 mg fostemsavir once daily for at least 96 weeks

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 400 mg raltegravir twice daily for at least 96 weeks

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 300 mg tenofovir once daily for at least 96 weeks

    Arm title
    		 FTR 1200 mg QD/RAL/TDF
    Arm description
    		 Participants were randomized and administered 1200 mg of FTR QD along (double-blind) with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomized to receive oral tablets of 400 and 800 twice daily and 600 and 1200 mg fostemsavir once daily for at least 96 weeks

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 400 mg raltegravir twice daily for at least 96 weeks

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 300 mg tenofovir once daily for at least 96 weeks

    Arm title
    		 ATV/r/RAL/TDF
    Arm description
    		 Participants were randomized to Reference group (open label) and administered ATV/r 300/100 mg once daily along with 400 mg RAL BID and 300 mg TDF QD.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atazanavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants randomized to reference group administered 300 mg atazanavir once daily for at least 96 weeks

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 100 mg ritonavir once daily for at least 96 weeks

    Investigational medicinal product name
    Raltegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 400 mg raltegravir twice daily for at least 96 weeks

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants administered 300 mg tenofovir once daily for at least 96 weeks

    Number of subjects in period 1 [1]
    		FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Started
    50
    49
    51
    50
    51
    Completed
    33
    25
    28
    22
    22
    Not completed
    17
    24
    23
    28
    29
         Physician decision
    1
    -
    -
    -
    -
         Prison
    -
    -
    1
    -
    -
         Continuation criteria not met
    -
    -
    1
    1
    -
         Sponsor terminated
    -
    -
    -
    -
    1
         As per Exclusion criteria
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    5
    5
    6
    7
    9
         Unable to come back for visit
    1
    -
    1
    1
    -
         Adverse event, non-fatal
    -
    3
    -
    2
    7
         Death
    1
    -
    1
    -
    -
         Pregnancy
    -
    1
    -
    -
    1
         Non-compliance with study drug
    1
    2
    6
    -
    2
         Missed End of treatment visit
    -
    -
    -
    1
    -
         Adhesion problem
    -
    -
    -
    1
    -
         Lost to follow-up
    5
    3
    3
    8
    5
         Investigator relocating
    -
    2
    -
    3
    1
         Early termination
    -
    -
    -
    -
    1
         Lack of efficacy
    3
    7
    4
    4
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Total 254 were randomized of which 251 participants were treated in Stage 1 Primary study, 2 participants withdrew consent and 1 was randomized in error.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FTR 400 mg BID/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 400 milligrams (mg) of FTR twice daily (BID) (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF once daily (QD) (open label).

    Reporting group title
    FTR 800 mg BID/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 800 mg of FTR BID (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    FTR 600 mg QD/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 600 mg of FTR QD (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    FTR 1200 mg QD/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 1200 mg of FTR QD along (double-blind) with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    ATV/r/RAL/TDF
    Reporting group description
    		 Participants were randomized to Reference group (open label) and administered ATV/r 300/100 mg once daily along with 400 mg RAL BID and 300 mg TDF QD.

    Reporting group values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF Total
    Number of subjects
    		 50 49 51 50 51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.1 ± 8.17 38.4 ± 9.49 40.1 ± 9.45 39.2 ± 11.41 39.7 ± 10.63 -
    Gender categorical
    Units: Subjects
        Female
    		 19 21 22 16 22 100
        Male
    		 31 28 29 34 29 151
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 14 15 16 18 13 76
        American Indian Or Alaska Native
    		 0 0 1 1 1 3
        Asian
    		 0 2 0 0 0 2
        White
    		 20 19 17 16 23 95
        Other/Mixed
    		 16 13 17 15 14 75

    End points

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    End points reporting groups
    Reporting group title
    FTR 400 mg BID/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 400 milligrams (mg) of FTR twice daily (BID) (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF once daily (QD) (open label).

    Reporting group title
    FTR 800 mg BID/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 800 mg of FTR BID (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    FTR 600 mg QD/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 600 mg of FTR QD (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    FTR 1200 mg QD/RAL/TDF
    Reporting group description
    		 Participants were randomized and administered 1200 mg of FTR QD along (double-blind) with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    ATV/r/RAL/TDF
    Reporting group description
    		 Participants were randomized to Reference group (open label) and administered ATV/r 300/100 mg once daily along with 400 mg RAL BID and 300 mg TDF QD.

    Primary: Percentage of participants with plasma HIV-1 Ribonucleic acid (RNA) < 50 Copies per milliliter (c/mL) at Week 24

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    End point title
    		 Percentage of participants with plasma HIV-1 Ribonucleic acid (RNA) < 50 Copies per milliliter (c/mL) at Week 24 [1]
    End point description
    Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 24 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to evaluate the antiviral activity. Treatment comparisons were not performed as this was an estimation study. Response rates were tabulated by treatment arm with exact Clopper-Pearson binomial 95 percentage confidence intervals (CI). Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the snapshot window of the visit of interest. Intent-To-Treat-Exposed (ITT-E) Population includes all randomized participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    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: There are no statistical data to report.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    50 [2]
    49 [3]
    51 [4]
    50 [5]
    51 [6]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants
    80 (66.3 to 90.0)
    69 (54.6 to 81.7)
    76 (62.5 to 87.2)
    72 (57.5 to 83.8)
    75 (60.4 to 85.7)
    Notes
    [2] - ITT-E Population
    [3] - ITT-E Population
    [4] - ITT-E Population
    [5] - ITT-E Population
    [6] - ITT-E Population
    No statistical analyses for this end point

    Primary: Number of participants with serious adverse events (SAE) and discontinuation due to AEs up to Week 24

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    End point title
    		 Number of participants with serious adverse events (SAE) and discontinuation due to AEs up to Week 24 [7]
    End point description
    Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. AEs leading to discontinuation of study therapy were also reported as safety assessment. Safety population included all participants who received at least one dose of study treatment. Summaries of SAEs and AEs leading to discontinuation or withdrawal through Week 24 included AEs with onset on or after the start of study treatment (i.e. study date of first study treatment intake) up to and including the end of the Week 24 visit snapshot window.
    End point type
    Primary
    End point timeframe
    Up to 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: There are no statistical data to report.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    50 [8]
    49 [9]
    51 [10]
    50 [11]
    51 [12]
    Units: Participants
        SAE
    3
    4
    4
    2
    5
        AEs leading to discontinuation
    1
    2
    0
    1
    2
    Notes
    [8] - Safety Population
    [9] - Safety Population
    [10] - Safety Population
    [11] - Safety Population
    [12] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from monotherapy Baseline in log10 HIV RNA

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    End point title
    		 Change from monotherapy Baseline in log10 HIV RNA [13]
    End point description
    Change from monotherapy Baseline in log10 HIV RNA to assess the antiviral activity of temsavir following administration of selected doses of FTR administered orally to HIV-1-infected participants for 7 days. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as value at indicated time point minus Baseline value. ITT-E Monotherapy Population comprised of participants that were randomized and participated in the monotherapy sub-study and received at least one dose of FTR Monotherapy. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and up to Day 8 of the monotherapy period
    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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF
    Number of subjects analysed
    7 [14]
    5 [15]
    10 [16]
    10 [17]
    Units: log10 c/mL
    arithmetic mean (standard deviation)
        Day 2, n=7, 5, 10, 9
    0.220 ± 0.1630
    0.149 ± 0.1820
    0.126 ± 0.1811
    0.126 ± 0.4216
        Day 5, n=7, 4, 10, 10
    -0.340 ± 0.3185
    -0.811 ± 0.3455
    -0.593 ± 0.2429
    -0.767 ± 0.6388
        Day 6, n=7, 5, 10, 10
    -0.530 ± 0.3170
    -1.082 ± 0.3388
    -0.822 ± 0.3076
    -1.053 ± 0.7491
        Day 7, n=6, 5, 10, 10
    -0.556 ± 0.4264
    -1.443 ± 0.4484
    -1.086 ± 0.4216
    -1.198 ± 0.6863
        Day 8, n=6, 4, 9, 9
    -0.691 ± 0.5380
    -1.372 ± 0.3208
    -1.218 ± 0.3902
    -1.470 ± 0.6570
    Notes
    [14] - ITT-E Monotherapy Population
    [15] - ITT-E Monotherapy Population
    [16] - ITT-E Monotherapy Population
    [17] - ITT-E Monotherapy Population
    No statistical analyses for this end point

    Secondary: Maximum decrease from monotherapy Baseline in log10 plasma HIV-1 RNA

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    End point title
    		 Maximum decrease from monotherapy Baseline in log10 plasma HIV-1 RNA [18]
    End point description
    Maximum decrease from monotherapy Baseline in log10 plasma HIV-1 RNA during monotherapy to assess the antiviral activity of temsavir following administration of selected doses of FTR administered orally to HIV-1-infected participants for 7 days. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as value at indicated time point minus Baseline value. The data for monotherapy nadir has been presented where nadir represents the maximum decrease from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Day 8 of the monotherapy period
    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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF
    Number of subjects analysed
    7 [19]
    5 [20]
    10 [21]
    10 [22]
    Units: log10 c/mL
    arithmetic mean (standard deviation)
        log10 c/mL
    -0.770 ± 0.4487
    -1.524 ± 0.3898
    -1.250 ± 0.3818
    -1.399 ± 0.6688
    Notes
    [19] - ITT-E Monotherapy Population
    [20] - ITT-E Monotherapy Population
    [21] - ITT-E Monotherapy Population
    [22] - ITT-E Monotherapy Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with plasma HIV-1 RNA < 50 c/mL at Day 8 of the monotherapy period

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    End point title
    		 Percentage of participants with plasma HIV-1 RNA < 50 c/mL at Day 8 of the monotherapy period [23]
    End point description
    Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Baseline of combination therapy was assessed to evaluate the antiviral activity of four doses of FTR. Baseline of combination therapy was the Day 1 of the combination therapy. Virologic success or failure was determined using the non-missing viral load value at Baseline of combination therapy. The assessment closest to the window target Study Day was used for the analysis. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Day 8 of the monotherapy period
    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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF
    Number of subjects analysed
    6 [24]
    4 [25]
    9 [26]
    9 [27]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants
    0 (0.0 to 45.9)
    0 (0.0 to 60.2)
    0 (0.0 to 33.6)
    11 (0.3 to 48.2)
    Notes
    [24] - ITT-E Monotherapy Population
    [25] - ITT-E Monotherapy Population
    [26] - ITT-E Monotherapy Population
    [27] - ITT-E Monotherapy Population
    No statistical analyses for this end point

    Secondary: Number of participants with SAE and discontinuation due to AEs during monotherapy period

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    End point title
    		 Number of participants with SAE and discontinuation due to AEs during monotherapy period [28]
    End point description
    Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. AEs leading to discontinuation of study therapy were also reported as safety assessment.
    End point type
    Secondary
    End point timeframe
    Up to Day 8 of the monotherapy period
    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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF
    Number of subjects analysed
    7 [29]
    5 [30]
    10 [31]
    10 [32]
    Units: Participants
        SAE
    0
    0
    0
    0
        AEs leading to discontinuation
    0
    0
    0
    0
    Notes
    [29] - ITT-E Monotherapy Population
    [30] - ITT-E Monotherapy Population
    [31] - ITT-E Monotherapy Population
    [32] - ITT-E Monotherapy Population
    No statistical analyses for this end point

    Secondary: Change from monotherapy Baseline in Cluster of Differentiation (CD)4+ and CD8+ T-cell counts during monotherapy

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    End point title
    		 Change from monotherapy Baseline in Cluster of Differentiation (CD)4+ and CD8+ T-cell counts during monotherapy [33]
    End point description
    Blood was collected and CD4+ and CD8+ cell count assessment was done by flow cytometery and was carried out at Baseline (Day 1) to evaluate the immunological activity of multiple doses of FTR. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and the values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF
    Number of subjects analysed
    5 [34]
    4 [35]
    8 [36]
    8 [37]
    Units: Cells per cubic millimeter
    arithmetic mean (standard deviation)
        CD4+
    58.4 ± 81.60
    134.8 ± 25.70
    71.8 ± 117.68
    63.4 ± 100.86
        CD8+
    134.2 ± 180.64
    216.3 ± 215.57
    188.0 ± 363.58
    67.6 ± 236.55
    Notes
    [34] - ITT-E Monotherapy Population
    [35] - ITT-E Monotherapy Population
    [36] - ITT-E Monotherapy Population
    [37] - ITT-E Monotherapy Population
    No statistical analyses for this end point

    Secondary: Change from monotherapy Baseline in CD4+ and CD8+ T-cell proportion during monotherapy

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    End point title
    		 Change from monotherapy Baseline in CD4+ and CD8+ T-cell proportion during monotherapy [38]
    End point description
    Blood was collected and CD4+ and CD8+ proportion assessment was done by flow cytometery and was carried out at Baseline (Day 1) to evaluate the immunological activity of multiple doses of FTR. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and the values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 8
    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: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF
    Number of subjects analysed
    6 [39]
    4 [40]
    9 [41]
    8 [42]
    Units: cells per cubic millimeter
    arithmetic mean (standard deviation)
        CD4+
    -0.005 ± 0.0084
    0.023 ± 0.0299
    0.008 ± 0.0335
    0.014 ± 0.0320
        CD8+
    -0.003 ± 0.0273
    -0.040 ± 0.0245
    -0.009 ± 0.0465
    -0.021 ± 0.0364
    Notes
    [39] - ITT-E Monotherapy Population
    [40] - ITT-E Monotherapy Population
    [41] - ITT-E Monotherapy Population
    [42] - ITT-E Monotherapy Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with plasma HIV-1 RNA < 50 c/mL at primary study

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    End point title
    		 Percentage of participants with plasma HIV-1 RNA < 50 c/mL at primary study
    End point description
    Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Weeks 48 and 96 using the FDA snapshot algorithm was assessed to evaluate the antiviral activity. Treatment comparisons were not performed as this was an estimation study. Response rates were tabulated by treatment arm with exact Clopper-Pearson binomial 95 percentage CI. Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the snapshot window of the visit of interest.
    End point type
    Secondary
    End point timeframe
    Weeks 48 and 96
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    50 [43]
    49 [44]
    51 [45]
    50 [46]
    51 [47]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Week 48
    82 (68.6 to 91.4)
    61 (46.2 to 74.8)
    69 (54.1 to 80.9)
    68 (53.3 to 80.5)
    71 (56.2 to 82.5)
        Week 96
    78 (64.0 to 88.5)
    49 (34.4 to 63.7)
    63 (48.1 to 75.9)
    58 (43.2 to 71.8)
    57 (42.2 to 70.7)
    Notes
    [43] - ITT-E Population
    [44] - ITT-E Population
    [45] - ITT-E Population
    [46] - ITT-E Population
    [47] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with SAE and discontinuation due to AEs during primary study

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    End point title
    		 Number of participants with SAE and discontinuation due to AEs during primary study
    End point description
    Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or suspected transmission of an infectious agent via the study drug were categorized as SAE. AEs leading to discontinuation of study therapy were also reported as safety assessment. Safety Population comprised of participants who received at least one dose of study treatment. Summaries of SAEs and AEs leading to discontinuation or withdrawal through Week X (where X = 48 or 96) included AEs with onset on or after the start of study treatment (i.e. study date of first study treatment intake) up to and including the end of the Week 48 and 96 visit snapshot window.
    End point type
    Secondary
    End point timeframe
    Weeks 48 and 96
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    50 [48]
    49 [49]
    51 [50]
    50 [51]
    51 [52]
    Units: Participants
        SAE, Week 48
    3
    5
    4
    2
    5
        SAE, Week 96
    5
    7
    6
    4
    7
        AEs leading to discontinuation, Week 48
    1
    2
    0
    1
    3
        AEs leading to discontinuation, Week 96
    1
    2
    0
    2
    5
    Notes
    [48] - Safety Population
    [49] - Safety Population
    [50] - Safety Population
    [51] - Safety Population
    [52] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ T-cell count

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    End point title
    		 Change from Baseline in CD4+ T-cell count
    End point description
    Blood was collected and CD4+ cell count assessment by flow cytometery was carried out at Baseline (Day 1), Weeks 24, 48 and 96 to evaluate the immunological activity of multiple doses of BMS-663068/GSK3684934. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 24, 48 and 96
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    50 [53]
    49 [54]
    51 [55]
    50 [56]
    51 [57]
    Units: Cells per cubic millimeter
    arithmetic mean (standard deviation)
        Week 24, n=41, 38, 48, 42, 40
    134.3 ± 84.63
    111.0 ± 123.75
    109.5 ± 87.20
    124.5 ± 111.04
    119.4 ± 142.85
        Week 48, n=43, 34, 43, 41, 41
    199.1 ± 124.24
    158.7 ± 118.70
    140.5 ± 97.16
    155.4 ± 107.06
    178.7 ± 133.90
        Week 96, n=42, 28, 35, 28, 31
    264.6 ± 147.83
    210.8 ± 158.03
    175.7 ± 98.28
    211.7 ± 151.03
    250.1 ± 217.54
    Notes
    [53] - ITT-E Population
    [54] - ITT-E Population
    [55] - ITT-E Population
    [56] - ITT-E Population
    [57] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with newly-emergent genotypic substitutions at Week 24

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    End point title
    		 Number of participants with newly-emergent genotypic substitutions at Week 24
    End point description
    Participants who administered antiretroviral (ARV) with virologic failure (VF) were assessed. Genotypic substitution included assessment of Reverse Transcriptase (RT) substitution, Protease Inhibitor (PI) substitution and Integrase RAL substitution as per International Acquired Immune Deficiency Syndrome (AIDS) Society-USA (IAS-USA) list. ITT-E Resistance Tested through Week 24 population included participants who met the criteria for Resistance testing, and the confirmatory value or value at discontinuation occurred at or before the end of the Week 24 Snapshot analysis window. The criteria for resistance tested was participant who had virologic failure or met the following criteria a) Participants who achieved viral suppression (plasma HIV-1 RNA < 50 c/mL) and have confirmed plasma HIV-1 RNA >= 400 c/mL at any time during the study. b) Participants who were discontinued before achieving viral suppression (plasma HIV-1 RNA < 50 c/mL) after Week 8 with last plasma HIV-1 RNA >=400 c/mL.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    3 [58]
    7 [59]
    11 [60]
    3 [61]
    5 [62]
    Units: Participants
        PI substitution
    0
    0
    0
    0
    0
        RT substitution
    0
    0
    0
    1
    0
        Integrase substitution
    0
    0
    1
    1
    0
    Notes
    [58] - ITT-E Resistance Tested through Week 24 Population
    [59] - ITT-E Resistance Tested through Week 24 Population
    [60] - ITT-E Resistance Tested through Week 24 Population
    [61] - ITT-E Resistance Tested through Week 24 Population
    [62] - ITT-E Resistance Tested through Week 24 Population
    No statistical analyses for this end point

    Secondary: Number of participants with newly-emergent genotypic substitutions at Week 48

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    End point title
    		 Number of participants with newly-emergent genotypic substitutions at Week 48
    End point description
    Participants who administered ARV with VF were assessed. Genotypic substitution included assessment of RT substitution, PI substitution and Integrase RAL substitution as per IAS-USA list. ITT-E Resistance Tested through Week 48 population included participants who met the criteria for Resistance testing, and the confirmatory value or value at discontinuation occurred at or before the end of the Week 48 Snapshot analysis window. The criteria for resistance tested was participant who had virologic failure or the following criteria a) Participants who achieved viral suppression (plasma HIV-1 RNA < 50 c/mL) and have confirmed plasma HIV-1 RNA >= 400 c/mL at any time during the study. b) Participants who were discontinued before achieving viral suppression (plasma HIV-1 RNA < 50 c/mL) after Week 8 with last plasma HIV-1 RNA >=400 c/mL.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    9 [63]
    10 [64]
    16 [65]
    9 [66]
    6 [67]
    Units: Participants
        PI substitution
    1
    0
    0
    1
    0
        RT substitution
    0
    0
    0
    2
    0
        Integrase substitution
    1
    1
    1
    2
    0
    Notes
    [63] - ITT-E Resistance Tested through Week 48 Population
    [64] - ITT-E Resistance Tested through Week 48 Population
    [65] - ITT-E Resistance Tested through Week 48 Population
    [66] - ITT-E Resistance Tested through Week 48 Population
    [67] - ITT-E Resistance Tested through Week 48 Population
    No statistical analyses for this end point

    Secondary: Number of participants with newly-emergent genotypic substitutions at Week 96

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    End point title
    		 Number of participants with newly-emergent genotypic substitutions at Week 96
    End point description
    Participants who administered ARV with VF were assessed. Genotypic substitution included assessment of RT substitution, PI substitution and Integrase RAL substitution as per IAS-USA list. ITT-E Resistance Tested through Week 96 population included participants who met the criteria for Resistance testing, and the confirmatory value or value at discontinuation occurred at or before the end of the Week 96 Snapshot analysis window. The criteria for resistance tested was participants with virologic failure or the following criteria a) Participants who achieved viral suppression (plasma HIV-1 RNA < 50 c/mL) and have confirmed plasma HIV-1 RNA >= 400 c/mL at any time during the study. b) Participants who were discontinued before achieving viral suppression (plasma HIV-1 RNA < 50 c/mL) after Week 8 with last plasma HIV-1 RNA >=400 c/mL.
    End point type
    Secondary
    End point timeframe
    Up to Week 96
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    20 [68]
    18 [69]
    23 [70]
    13 [71]
    11 [72]
    Units: Participants
        PI substitution
    3
    1
    2
    2
    0
        RT substitution
    2
    1
    2
    2
    1
        Integrase RAL substitution
    2
    2
    1
    3
    0
    Notes
    [68] - ITT-E Resistance Tested through Week 96 Population
    [69] - ITT-E Resistance Tested through Week 96 Population
    [70] - ITT-E Resistance Tested through Week 96 Population
    [71] - ITT-E Resistance Tested through Week 96 Population
    [72] - ITT-E Resistance Tested through Week 96 Population
    No statistical analyses for this end point

    Secondary: Maximum change from Baseline in Inhibitory Concentration at 50% (IC50) fold change among participants with VF at Week 24

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    End point title
    		 Maximum change from Baseline in Inhibitory Concentration at 50% (IC50) fold change among participants with VF at Week 24
    End point description
    Virologic failure is defined clinically as confirmed plasma HIV-1 RNA >= 50 copies/mL at Week 24 or later or virologic rebound defined as confirmed HIV-1 RNA >=50 copies/mL at any time after prior confirmed suppression to <50 copies/mL OR confirmed >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level where nadir was >= 50 copies/mL . The phenotypic resistance to a drug is defined as a fold change (i.e, ratio of the IC50 of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. Maximum change from Baseline in Temsavir IC50 fold change based on all on-treatment values has been presented. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 24
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    3 [73]
    4 [74]
    6 [75]
    2 [76]
    2 [77]
    Units: IC50 Fold Change
    arithmetic mean (standard deviation)
        IC50 Fold Change
    -2.350 ± 3.4536
    1014.748 ± 2015.5876
    101.627 ± 190.4849
    39.030 ± 55.1119
    -0.030 ± 0.6364
    Notes
    [73] - ITT-E Resistance Tested through Week 24 Population
    [74] - ITT-E Resistance Tested through Week 24 Population
    [75] - ITT-E Resistance Tested through Week 24 Population
    [76] - ITT-E Resistance Tested through Week 24 Population
    [77] - ITT-E Resistance Tested through Week 24 Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in IC50 fold change among participants with VF at Week 48

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    End point title
    		 Change from Baseline in IC50 fold change among participants with VF at Week 48
    End point description
    Virologic failure is defined clinically as confirmed plasma HIV-1 RNA >= 50 copies/mL at Week 24 or later or later or virologic rebound defined as confirmed HIV-1 RNA >=50 copies/mL at any time after prior confirmed suppression to <50 copies/mL OR confirmed >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level where nadir was >= 50 copies/mL. The phenotypic resistance to a drug is defined as a fold change (i.e, ratio of the IC50 of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. Maximum change from Baseline in Temsavir IC50 fold change based on all on-treatment values has been presented. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 48
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    5 [78]
    7 [79]
    8 [80]
    5 [81]
    4 [82]
    Units: IC50 Fold Change
    arithmetic mean (standard deviation)
        IC50 Fold Change
    -2.624 ± 3.2819
    586.776 ± 1521.9126
    81.729 ± 165.4931
    449.092 ± 647.9828
    1.020 ± 1.4770
    Notes
    [78] - ITT-E Resistance Tested through Week 48 Population
    [79] - ITT-E Resistance Tested through Week 48 Population
    [80] - ITT-E Resistance Tested through Week 48 Population
    [81] - ITT-E Resistance Tested through Week 48 Population
    [82] - ITT-E Resistance Tested through Week 48 Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in IC50 fold change among participants with VF at Week 96

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    End point title
    		 Change from Baseline in IC50 fold change among participants with VF at Week 96
    End point description
    Virologic failure is defined clinically as confirmed plasma HIV-1 RNA >= 50 copies/mL at Week 24 or later or virologic rebound defined as confirmed HIV-1 RNA >=50 copies/mL at any time after prior confirmed suppression to <50 copies/mL OR confirmed >1 log10 copies/mL increase in HIV-1 RNA at any time above nadir level where nadir was >= 50 copies/mL. The phenotypic resistance to a drug is defined as a fold change (i.e, ratio of the IC50 of the clinical isolate to the IC50 of the reference strain) greater than the cut-off for reduced susceptibility. Maximum change from Baseline in Temsavir IC50 fold change based on all on-treatment values has been presented. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment and those values are absolute values. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 96
    End point values
    		 FTR 400 mg BID/RAL/TDF FTR 800 mg BID/RAL/TDF FTR 600 mg QD/RAL/TDF FTR 1200 mg QD/RAL/TDF ATV/r/RAL/TDF
    Number of subjects analysed
    6 [83]
    14 [84]
    11 [85]
    9 [86]
    4 [87]
    Units: IC50 Fold Change
    arithmetic mean (standard deviation)
        IC50 Fold Change
    25.480 ± 68.9030
    419.901 ± 1092.5929
    46.351 ± 157.9219
    777.818 ± 1550.8887
    1.090 ± 1.5444
    Notes
    [83] - ITT-E Resistance Tested through Week 96 Population
    [84] - ITT-E Resistance Tested through Week 96 Population
    [85] - ITT-E Resistance Tested through Week 96 Population
    [86] - ITT-E Resistance Tested through Week 96 Population
    [87] - ITT-E Resistance Tested through Week 96 Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from start of study treatment (Day 1) until 2117 days
    Adverse event reporting additional description
    The analysis was based on the Safety Population. Adverse events data were not reported cumulatively for all intervention concentrations, and were only reported cumulatively per FTR or ATV/r interventions.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    FTR/RAL/TDF Total
    Reporting group description
    		 All participants who were randomized to receive either of FTR 400mg BID, 800 mg BID, 600mg QD or 1200 mg QD (double-blind) along with 400 mg RAL BID (open label) and 300 mg TDF QD (open label).

    Reporting group title
    ATV/r/RAL/TDF
    Reporting group description
    		 Participants were randomized to Reference group (open label) and administered ATV/r 300/100 mg once daily along with 400 mg RAL BID and 300 mg TDF QD.

    Serious adverse events
    		 FTR/RAL/TDF Total ATV/r/RAL/TDF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 200 (17.50%)
    8 / 51 (15.69%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of salivary gland
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Obstructive airways disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bone tuberculosis
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 51 (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
    		 FTR/RAL/TDF Total ATV/r/RAL/TDF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    163 / 200 (81.50%)
    46 / 51 (90.20%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    9 / 200 (4.50%)
    3 / 51 (5.88%)
         occurrences all number
    16
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 200 (3.00%)
    4 / 51 (7.84%)
         occurrences all number
    6
    6
    Blood bilirubin increased
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 51 (7.84%)
         occurrences all number
    1
    9
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 200 (7.50%)
    3 / 51 (5.88%)
         occurrences all number
    16
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 200 (19.00%)
    6 / 51 (11.76%)
         occurrences all number
    64
    18
    Dizziness
         subjects affected / exposed
    9 / 200 (4.50%)
    4 / 51 (7.84%)
         occurrences all number
    9
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 200 (5.50%)
    4 / 51 (7.84%)
         occurrences all number
    14
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    37 / 200 (18.50%)
    10 / 51 (19.61%)
         occurrences all number
    48
    16
    Nausea
         subjects affected / exposed
    19 / 200 (9.50%)
    6 / 51 (11.76%)
         occurrences all number
    22
    18
    Vomiting
         subjects affected / exposed
    16 / 200 (8.00%)
    6 / 51 (11.76%)
         occurrences all number
    18
    8
    Abdominal pain
         subjects affected / exposed
    13 / 200 (6.50%)
    4 / 51 (7.84%)
         occurrences all number
    13
    6
    Dyspepsia
         subjects affected / exposed
    12 / 200 (6.00%)
    2 / 51 (3.92%)
         occurrences all number
    13
    2
    Constipation
         subjects affected / exposed
    11 / 200 (5.50%)
    0 / 51 (0.00%)
         occurrences all number
    12
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    11 / 51 (21.57%)
         occurrences all number
    0
    35
    Jaundice
         subjects affected / exposed
    0 / 200 (0.00%)
    8 / 51 (15.69%)
         occurrences all number
    0
    9
    Ocular icterus
         subjects affected / exposed
    1 / 200 (0.50%)
    7 / 51 (13.73%)
         occurrences all number
    1
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 200 (8.50%)
    2 / 51 (3.92%)
         occurrences all number
    21
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    15 / 200 (7.50%)
    0 / 51 (0.00%)
         occurrences all number
    21
    0
    Alopecia
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 200 (6.50%)
    2 / 51 (3.92%)
         occurrences all number
    16
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    20 / 200 (10.00%)
    3 / 51 (5.88%)
         occurrences all number
    25
    3
    Arthralgia
         subjects affected / exposed
    18 / 200 (9.00%)
    1 / 51 (1.96%)
         occurrences all number
    22
    1
    Pain in extremity
         subjects affected / exposed
    14 / 200 (7.00%)
    1 / 51 (1.96%)
         occurrences all number
    17
    1
    Myalgia
         subjects affected / exposed
    10 / 200 (5.00%)
    0 / 51 (0.00%)
         occurrences all number
    10
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    32 / 200 (16.00%)
    5 / 51 (9.80%)
         occurrences all number
    52
    10
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 200 (13.50%)
    7 / 51 (13.73%)
         occurrences all number
    47
    7
    Urinary tract infection
         subjects affected / exposed
    28 / 200 (14.00%)
    6 / 51 (11.76%)
         occurrences all number
    62
    19
    Influenza
         subjects affected / exposed
    22 / 200 (11.00%)
    7 / 51 (13.73%)
         occurrences all number
    43
    8
    Bronchitis
         subjects affected / exposed
    22 / 200 (11.00%)
    4 / 51 (7.84%)
         occurrences all number
    34
    4
    Pharyngitis
         subjects affected / exposed
    17 / 200 (8.50%)
    5 / 51 (9.80%)
         occurrences all number
    19
    5
    Herpes zoster
         subjects affected / exposed
    17 / 200 (8.50%)
    2 / 51 (3.92%)
         occurrences all number
    20
    2
    Gastroenteritis
         subjects affected / exposed
    11 / 200 (5.50%)
    6 / 51 (11.76%)
         occurrences all number
    11
    6
    Lower respiratory tract infection
         subjects affected / exposed
    10 / 200 (5.00%)
    1 / 51 (1.96%)
         occurrences all number
    12
    1
    Onychomycosis
         subjects affected / exposed
    8 / 200 (4.00%)
    3 / 51 (5.88%)
         occurrences all number
    8
    3
    Sinusitis
         subjects affected / exposed
    5 / 200 (2.50%)
    4 / 51 (7.84%)
         occurrences all number
    12
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2011
    Amendment 01: Permit the collection and storage of blood samples for use in future exploratory pharmacogenetic research. The sponsor may use deoxyribonucleic acid (DNA) obtained from the blood sample and health information collected from the main clinical study to study the association between genetic variation and drug response. The sponsor could also use the DNA to study the causes and further progression of HIV-1 infections. Samples from this study could also be used in conjunction with pharmacogenetic research results from other clinical studies to accomplish this objective.
    05 Feb 2013
    Amendment 02: 1. Remove all 4 of the required visits in the 24 weeks of the post-dosing follow-up period. 2. Add an optional visit at post-dosing Week 2, intended primarily for the collection of a blood sample for the assessment of Neutralizing Antibody Potency, for those participants who meet the criteria for participation. 3. Modify the description of the Neutralizing Antibody Potency analysis. 4. Table numbering has been modified in accordance with new sponsor Core Template standards.
    08 Dec 2014
    Amendment 03: 1. Add Pregnancy Testing for WOCBP every 4 weeks during Stage 2. 2. Add Telephone Contact Visits (and supporting text) between Stage 2 visits for adherence assessments. 3. Indicated adherence issues of < 90 percentage will be assessed closely. 4. Clarified that participants with a confirmed viral load that requires study discontinuation may remain on study therapies until resistance results are available. 5. Corrected references to other sections in the protocol: In Section 3.5, the reference in the 8th bullet to Section 6.6.1.5 was corrected to 6.7.1.5. In Table 5.1-3, the reference in the Intensive PK and Sparse PK rows to Section 5.5.3 was corrected to 5.5.2. In Section 5.3, the reference to 6.6.1 was corrected to 6.7.1.
    04 Feb 2016
    Amendment 04: Section 4.1, Study Treatments - Table 4-1.1, Added: first row to table showing the details of the new formulation Updated: Storage conditions for Raltegravir tablet and Tenofovir tablet.
    25 Oct 2016
    Amendment 05: 1. Identify ViiV Healthcare Company (ViiV Healthcare) as the Sponsor and removed references to Bristol-Myers Squibb (BMS). 2. Acknowledge that GlaxoSmithKline (GSK) and ICON plc are supporting ViiV Healthcare in the conduct of the study. 3. Include the GSK study number (205889). 4. Include the GSK compound number (GSK3684934) and metabolite number (GSK2616713). 5. Indicate that molecular analysis will occur at ViiV Healthcare Discovery (Wallingford, CT, USA) instead of at BMS. 6. Updated Sponsor Information and included ICON Medical Monitor Emergency Contact information. 7. Other minor edits were made to improve the readability of the document.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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