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    Clinical Trial Results:
    A Phase III Randomized, Double-blind Study of the Safety and Efficacy of GSK1349572 50 mg Once Daily Versus Raltegravir 400 mg Twice Daily, Both Administered with an Investigator selected Background Regimen Over 48 Weeks in HIV-1 Infected, Integrase Inhibitor-Naïve, Antiretroviral Therapy-Experienced Adults

    Summary
    EudraCT number
    		 2009-018001-51
    Trial protocol
    		 ES   FR   BE   NL   GB   GR   IT   HU   PL  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    18 Sep 2020
    First version publication date
    18 Sep 2020
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    111762
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ViiV Healthcare
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, ViiV Healthcare, 1 8664357343, GSKClinicalSupportHD@GSK.com
    Scientific contact
    GSK Response Center, ViiV Healthcare, 1 8664357343,
    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
    Interim
    Date of interim/final analysis
    22 Mar 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Feb 2013
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the antiviral efficacy of GSK1349572 50 mg once daily compared to RAL 400 mg BID both in combination with a background regimen consisting of one to two (1-2) fully active single agents in HIV-1 infected, integrase inhibitor-naïve, therapy experienced subjects at 48 weeks.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Oct 2010
    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: 47
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 125
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Chile: 25
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Mexico: 41
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    South Africa: 100
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 227
    Worldwide total number of subjects
    719
    EEA total number of subjects
    99
    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)
    707
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1441 participants were screened; 724 were randomized. A total of 719 participants received at least 1 dose of study medication and comprised the intent-to-treat exposed (ITT-E) population. Four participants from one closed site were removed from the ITT-E population creating the modified ITT-E population with 715 participants.

    Period 1
    Period 1 title
    48 Week Double-blind Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTG 50 mg OD
    Arm description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continue to have access to DTG in the Open-Label phase of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTG 50 mg OD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received GSK1349572 50mg OD plus raltegravir placebo BID.

    Arm title
    		 RAL 400 mg BID
    Arm description
    		 Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GSK will continue to supply RAL in the Open-Label Phase until it is commercially available.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    RAL 400 mg BID
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received raltegravir 400mg BID plus GSK1349572 placebo OD.

    Number of subjects in period 1
    		DTG 50 mg OD RAL 400 mg BID
    Started
    357
    362
    Completed
    299
    283
    Not completed
    58
    79
         Physician decision
    1
    1
         Consent withdrawn by subject
    11
    5
         Site Closed
    3
    1
         Adverse event, non-fatal
    4
    11
         Met Protocol-Defined Stopping Criteria
    5
    3
         Lost to follow-up
    5
    10
         Lack of efficacy
    20
    42
         Protocol deviation
    9
    6
    Period 2
    Period 2 title
    Open-label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTG 50 mg OD
    Arm description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continue to have access to DTG in the Open-Label phase of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTG 50 mg OD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive GSK1349572 50mg OD plus raltegravir placebo BID.

    Arm title
    		 RAL 400 mg BID
    Arm description
    		 Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GSK will continue to supply RAL in the Open-Label Phase until it is commercially available.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    RAL 400 mg BID
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects will receive raltegravir 400mg BID plus GSK1349572 placebo OD.

    Number of subjects in period 2 [1]
    		DTG 50 mg OD RAL 400 mg BID
    Started
    295
    27
    Ongoing at the time of analysis
    282
    23
    Completed
    0
    1
    Not completed
    295
    26
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    3
    -
         Lack of efficacy
    7
    3
         Protocol deviation
    2
    -
         Ongoing at the time of analysis
    282
    23
    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: A total of 322 out of 582 participants who completed double-blinded phase opted to continue open-label phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    48 Week Double-blind Phase
    Reporting group description
    		 Participants were randomized to 1:1 ratio to receive dolutegravir (DTG) 50 milligram (mg) once daily or raltegravir (RAL) 400 mg twice daily for 48 Weeks.

    Reporting group values
    		 48 Week Double-blind Phase Total
    Number of subjects
    		 719
    Age categorical
    Baseline Characteristic data are reported for members of the modified Intent-To-Treat Exposed Population, all randomized participants who received at least one dose of IP excluding four participants at one site, which was closed due to Good Clinical Practice (GCP) non-compliance issues in another ViiV sponsored trial.
    Units: Subjects
    Age continuous
    Baseline Characteristic data are reported for members of the modified Intent-To-Treat Exposed Population, all randomized participants who received at least one dose of IP excluding four participants at one site, which was closed due to Good Clinical Practice (GCP) non-compliance issues in another ViiV sponsored trial.
    Units: years
        arithmetic mean (standard deviation)
    		 42.5 ( 10.13 ) -
    Gender categorical
    Baseline Characteristic data are reported for members of the modified Intent-To-Treat Exposed Population, all randomized participants who received at least one dose of IP excluding four participants at one site, which was closed due to Good Clinical Practice (GCP) non-compliance issues in another ViiV sponsored trial.
    Units: Subjects
        Male
    		 485 485
        Female
    		 230 230
        Missing
    		 4 4
    Race/Ethnicity, Customized
    Measure Description: Baseline Characteristic data are reported for members of the modified Intent-To-Treat Exposed Population, all randomized participants who received at least one dose of IP excluding four participants at one site, which was closed due to Good Clinical Practice (GCP) non-compliance issues in another ViiV sponsored trial.
    Units: Subjects
        African American/African Heritage
    		 303 303
        American Indian or Alaska Native
    		 27 27
        Asian-Central/South Asian Heritage
    		 4 4
        Asian-East Asian Heritage
    		 10 10
        Asian-South East Asian Heritage
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 1 1
        White-Arabic/North African Heritage
    		 6 6
        White-White/Caucasian/European Heritage
    		 347 347
        Mixed Race
    		 14 14
        Unknown
    		 2 2
        Missing
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    DTG 50 mg OD
    Reporting group description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continue to have access to DTG in the Open-Label phase of the study.

    Reporting group title
    RAL 400 mg BID
    Reporting group description
    		 Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GSK will continue to supply RAL in the Open-Label Phase until it is commercially available.
    Reporting group title
    DTG 50 mg OD
    Reporting group description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continue to have access to DTG in the Open-Label phase of the study.

    Reporting group title
    RAL 400 mg BID
    Reporting group description
    		 Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GSK will continue to supply RAL in the Open-Label Phase until it is commercially available.

    Primary: Percentage of participants with HIV-1 RNA <50 copies/milliliter (c/mL) at Week 48

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    End point title
    		 Percentage of participants with HIV-1 RNA <50 copies/milliliter (c/mL) at Week 48
    End point description
    The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 c/mL at Week 48 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the randomized phase of the study.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    354 [1]
    361 [2]
    Units: Percentage of participants
    71
    64
    Notes
    [1] - Modified Intent-To-Treat Exposed (mITT-E) Population
    [2] - mITT-E Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Non-inferiority of DTG 50 mg and RAL at Week 48 can be concluded if the lower bound of a two-sided 95% confidence interval (CI) for the difference in percentages (DTG - RAL) is greater than -12%. If non-inferiority were established, superiority would be tested at the nominal 5% level based on a pre-specified testing procedure.
    Comparison groups
    DTG 50 mg OD v RAL 400 mg BID
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.03 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 14.2
    Notes
    [3] - Analysis was adjusted for the BL stratification factors: HIV-1 RNA (<=50000 vs > 50000 c/mL), darunavir-ritonavir use without primary protease inhibitor mutations (yes vs no), and phenotypic susceptibility score (2 vs <2) to background regimen.
    [4] - P-value is for test of superiority. Adjusted difference in proportion which is based on the difference in percentage, adjusted for Baseline (BL) stratification factors.

    Secondary: Number of participants (par.) with detectable virus that has genotypic or phenotypic evidence of treatment-emergent INI resistance at time of protocol defined virology failure (PDVF)

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    End point title
    		 Number of participants (par.) with detectable virus that has genotypic or phenotypic evidence of treatment-emergent INI resistance at time of protocol defined virology failure (PDVF)
    End point description
    For par. meeting one of the criteria for PDVF, plasma samples collected at the time point of virologic failure and Baseline were tested to evaluate any potential genotypic and/or phenotypic evolution of resistance. PDVF was defined as (A) virologic non-response: a decrease in plasma HIV-1 RNA of <1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA is <400 copies/mL; confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24 or (B) virologic rebound: confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL; confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL.Treatment-emergent IN mutations are those detected at the time of PDVF but not at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline until PDVF up to Week 48
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    354 [5]
    361 [6]
    Units: Participants
    4
    17
    Notes
    [5] - mITT-E Population
    [6] - mITT-E Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 24

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    End point title
    		 Percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 24
    End point description
    The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <50 c/mL at Week 24 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at Week 24 as nonresponders, as well as participants who switched their concomitant ART prior to Week 24 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA measurement through Week 24 (within window) while the participant was on-treatment. The result below corresponds to the Week 24 interim analysis.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    354 [7]
    361 [8]
    Units: Percentage of participants
    79
    70
    Notes
    [7] - mITT-E Population
    [8] - mITT-E Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    DTG 50 mg OD v RAL 400 mg BID
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.003 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in percentage
    Point estimate
    9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 15.9
    Notes
    [9] - P-value is for test of superiority. Adjusted difference in proportion which is based on the difference in percentage, adjusted for Baseline (BL) stratification factors

    Secondary: Percentage of participants with plasma HIV-1 RNA <400 c/mL at Week 24 and Week 48

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    End point title
    		 Percentage of participants with plasma HIV-1 RNA <400 c/mL at Week 24 and Week 48
    End point description
    The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL at the visit of interest was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at the visit of interest as nonresponders, as well as participants who switched their concomitant ART prior to the visit of interest as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA measurment (within window) for the timepoint of interest while the participant was on-treatment.
    End point type
    Secondary
    End point timeframe
    Week 24, Week 48
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    354 [10]
    361 [11]
    Units: Percentage of Participants
        Week 24
    86
    79
        Week 48
    79
    71
    Notes
    [10] - mITT-E Population
    [11] - mITT-E Population
    No statistical analyses for this end point

    Secondary: Absolute values and change from Baseline in cluster of differentiation 4+ (CD4+) cell counts at Weeks 4, 8, 12, 16, 24, 32, 40, and 48

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    End point title
    		 Absolute values and change from Baseline in cluster of differentiation 4+ (CD4+) cell counts at Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point description
    The absolute value for CD4+ cell count (cells per millimeters cubed [mm^3]) was assessed at Baseline (BL), Week 4, Week 8, Week 12, Week 16, Week 24, Week 32, Week 40 and Week 48. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the indicated time points were assessed. Only those participants available at indicated time points were represented by n=X, X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    354 [12]
    361 [13]
    Units: cells/mm^3
    median (inter-quartile range (Q1-Q3))
        Absolute value, BL, n=354, 361
    204.5 (88 to 368)
    193.0 (96 to 365)
        Absolute value, Week 4, n=341, 351
    266.0 (164 to 416)
    253.0 (153 to 425)
        Absolute value, Week 8, n=338, 346
    280.0 (179 to 423)
    268.0 (163 to 445)
        Absolute value, Week 12, n=335, 345
    296.0 (188 to 451)
    289.0 (174 to 443)
        Absolute value, Week 16, n=327, 338
    299.0 (179 to 462)
    293.0 (186 to 460)
        Absolute value, Week 24, n=326, 326
    334.5 (201 to 488)
    326.5 (198 to 473)
        Absolute value, Week 32, n=309, 309
    332.0 (229 to 482)
    338.0 (215 to 484)
        Absolute value, Week 40, n=299, 292
    376.0 (239 to 523)
    349.0 (227 to 500)
        Absolute value, Week 48, n=294, 283
    385.0 (244 to 565)
    379.0 (250 to 521)
        Change from BL, Week 4, n=341, 351
    53.0 (0 to 109)
    45.0 (5 to 99)
        Change from BL, Week 8, n=338, 346
    60.5 (15 to 117)
    59.0 (12 to 124)
        Change from BL, Week 12, n=335, 345
    74.0 (25 to 135)
    75.0 (22 to 141)
        Change from BL, Week 16, n=327, 338
    76.0 (20 to 156)
    79.5 (28 to 158)
        Change from BL, Week 24, n=326, 326
    99.0 (34 to 184)
    93.0 (46 to 166)
        Change from BL, Week 32, n=309, 309
    107.0 (49 to 188)
    116.0 (52 to 173)
        Change from BL, Week 40, n=299, 292
    125.0 (57 to 212)
    117.5 (52 to 192)
        Change from BL, Week 48, n=294, 283
    144.0 (73 to 242)
    137.0 (67 to 224)
    Notes
    [12] - mITT-E Population
    [13] - mITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with indicated post-Baseline HIV-associated conditions, excluding recurrences, and disease progressions

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    End point title
    		 Number of participants with indicated post-Baseline HIV-associated conditions, excluding recurrences, and disease progressions
    End point description
    Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline (BS) to a CDC CAT C event (EV); CDC CAT B at BS to a CDC CAT C EV; CDC CAT C at BS to a new CDC CAT C EV; or CDC CAT A, B, or C at BS to death.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) until Week 48
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    354 [14]
    361 [15]
    Units: Participants
        Any CAT
    20
    19
        CAT B
    11
    11
        CAT C
    10
    6
        Death
    0
    3
        Progression from CAT A to CAT C
    2
    1
        Progression from CAT B to CAT C
    0
    1
        Progression from CAT C to New CAT C
    8
    3
        Progression from CAT A, B, or C to Death
    0
    3
    Notes
    [14] - mITT-E Population
    [15] - mITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated post-Baseline emergent Grade 1 to 4 clinical chemistry and hematology toxicities/laboratory adverse events (AEs)

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    End point title
    		 Number of participants with the indicated post-Baseline emergent Grade 1 to 4 clinical chemistry and hematology toxicities/laboratory adverse events (AEs)
    End point description
    All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death. .
    End point type
    Secondary
    End point timeframe
    From Baseline until Week 48, including participants with post-treatment events occurring after Week 48 for participants not entering the post-Week 48 Open-Label phase of the study
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    357 [16]
    362 [17]
    Units: Participants
        ALT
    47
    46
        Albumin
    4
    3
        ALP
    27
    42
        AST
    49
    52
        CO2 content/bicarbonate
    97
    109
        Cholesterol
    99
    103
        CK
    28
    29
        Creatinine
    18
    13
        Hyperglycaemia
    71
    80
        Hyperkalemia
    7
    6
        Hypernatremia
    5
    7
        Hypoglycaemia
    21
    14
        Hypokalemia
    37
    41
        Hyponatremia
    76
    79
        LDL cholesterol calculation
    68
    82
        Lipase
    63
    68
        Total bilirubin
    56
    53
        Triglycerides
    14
    24
        Hemoglobin
    19
    27
        Platelet count
    36
    32
        Total neutrophils
    49
    49
        White Blood Cell count
    19
    29
    Notes
    [16] - mITT-E Population
    [17] - mITT-E Population
    No statistical analyses for this end point

    Secondary: DTG PK parameters including Cmax, Cmin, C0, and C0_avg

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    End point title
    		 DTG PK parameters including Cmax, Cmin, C0, and C0_avg [18]
    End point description
    The maximal concentration (Cmax), and the minimal concentration (Cmin) were assessed by population pharmacokinetic (PK) modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48. DTG predose concentration (C0) at Week 4, Week 24, and Week 48 as well as the average C0 (C0_avg) , Cmax and Cmin were estimated and reported here. PK Concentration Population: all participants who received DTG, underwent sparse PK sampling during the study, and provided evaluable DTG plasma concentration data. Only those participants available at indicated time points were represented by n=X, X in the category titles.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 24, and Week 48
    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: There are no statistical data to report
    End point values
    		 DTG 50 mg OD
    Number of subjects analysed
    342 [19]
    Units: microgram/milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        C0, Week 4, Pre-dose, n=329
    0.786 ( 143 )
        C0, Week 24, Pre-dose, n=298
    0.940 ( 132 )
        C0, Week 48, Pre-dose, n=276
    0.932 ( 152 )
        C0_avg, n=342
    0.926 ( 131 )
        Cmax, n=340
    3.21 ( 26.7 )
        Cmin, n=340
    0.849 ( 76.5 )
    Notes
    [19] - PK Concentration Population
    No statistical analyses for this end point

    Secondary: DTG PK parameters including AUC(0-tau)

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    End point title
    		 DTG PK parameters including AUC(0-tau) [20]
    End point description
    AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure over time. AUC(0-tau) is defined as the area under the plasma concentration-time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval of DTG. AUC was assessed by population pharmacokinetic (PK) modeling using sparse PK samples which were collected as follows: one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 4, one pre-dose sample at Week 24, and one pre-dose sample and one post-dose sample at 1 to 3 hours/4 to 12 hours at Week 48.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 24, and Week 48
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are no statistical data to report
    End point values
    		 DTG 50 mg OD
    Number of subjects analysed
    340 [21]
    Units: Micrograms*hour per milliliter(µg*hr/mL)
        geometric mean (geometric coefficient of variation)
    44.7 ( 40.5 )
    Notes
    [21] - PK Concentration Population
    No statistical analyses for this end point

    Other pre-specified: Absolute values and change from Baseline in cluster of differentiation 8+ (CD8+) cell counts at Weeks 4, 8, 12, 16, 24, 32, 40, and 48

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    End point title
    		 Absolute values and change from Baseline in cluster of differentiation 8+ (CD8+) cell counts at Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point description
    The absolute value data for CD8+ cell count (cells per millimeters cubed [mm^3]) were only reported on a per-participant basis and were not summarized.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point values
    		 DTG 50 mg OD RAL 400 mg BID
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: cells/mm^3
        median (inter-quartile range (Q1-Q3))
    ( to )
    ( to )
    Notes
    [22] - Data was not summarized
    [23] - Data was not summarized
    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 AEs were collected from the start of study medication to the end of the randomized treatment period (up to Week 48).
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product. Also included are post-treatment events occurring after Week 48 for participants not entering the post-Week 48 Open-Label phase of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    RAL 400 mg BID
    Reporting group description
    		 Participants received matching DTG placebo OD + RAL 400 mg BID as AM and PM doses + investigator selected background ART therapy for 48 weeks. Participants were discontinued from the study after completion of the Week 48 visit unless a participant successfully completed Week 48 and RAL was not approved and commercially available within the country, GSK will continue to supply RAL in the Open-Label Phase until it is commercially available.

    Reporting group title
    DTG 50 mg OD
    Reporting group description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) once daily (OD) + matching Raltegravir (RAL) placebo twice daily (BID), one in the morning (AM dose) and one in the evening (PM dose) + investigator selected background antiretroviral (ART) therapy for 48 weeks. Participants who successfully completed 48 weeks of treatment continue to have access to DTG in the Open-Label phase of the study.

    Serious adverse events
    		 RAL 400 mg BID DTG 50 mg OD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 362 (11.60%)
    33 / 357 (9.24%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immunoblastic lymphoma
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval neoplasm
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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
    Alveolar proteinosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus disorder
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 362 (0.28%)
    4 / 357 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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
    Alcohol poisoning
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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
    Anaemia
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulation factor deficiency
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Methaemoglobinaemia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 362 (0.28%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral mucosal blistering
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 362 (0.28%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         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
    Rash pruritic
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 362 (0.28%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 362 (1.10%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 357 (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 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus oesophagitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrapulmonary tuberculosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gas gangrene
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histoplasmosis disseminated
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective myositis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Legionella infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parvovirus infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxoplasmosis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis liver
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 357 (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
    		 RAL 400 mg BID DTG 50 mg OD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    173 / 362 (47.79%)
    178 / 357 (49.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 362 (8.29%)
    33 / 357 (9.24%)
         occurrences all number
    34
    37
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    24 / 362 (6.63%)
    15 / 357 (4.20%)
         occurrences all number
    25
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    64 / 362 (17.68%)
    71 / 357 (19.89%)
         occurrences all number
    80
    96
    Nausea
         subjects affected / exposed
    29 / 362 (8.01%)
    29 / 357 (8.12%)
         occurrences all number
    36
    31
    Vomiting
         subjects affected / exposed
    20 / 362 (5.52%)
    20 / 357 (5.60%)
         occurrences all number
    30
    22
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 362 (6.63%)
    33 / 357 (9.24%)
         occurrences all number
    26
    35
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    18 / 362 (4.97%)
    19 / 357 (5.32%)
         occurrences all number
    18
    21
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 362 (8.01%)
    38 / 357 (10.64%)
         occurrences all number
    41
    44
    Influenza
         subjects affected / exposed
    25 / 362 (6.91%)
    24 / 357 (6.72%)
         occurrences all number
    31
    34
    Nasopharyngitis
         subjects affected / exposed
    22 / 362 (6.08%)
    23 / 357 (6.44%)
         occurrences all number
    23
    32
    Urinary tract infection
         subjects affected / exposed
    18 / 362 (4.97%)
    26 / 357 (7.28%)
         occurrences all number
    22
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2010
    Amendment 1: Country Specific Amendment for the United Kingdom
    14 Jan 2011
    Amendment 2: Primary reasons for this amendment include the addition of a Week 2 visit for all participants, and reference to an independent data monitoring committee (IDMC) which will regularly review targeted safety information; text was also added to allow use of entecavir for treatment of hepatitis B in appropriate clinical situations; minor clarifications and corrections have also been incorporated.
    15 Apr 2011
    Amendment 3: Country Specific Amendment for South Africa
    29 Aug 2011
    Amendment 4: Primary reasons for this amendment include: allowing the use of historical resistance test result in participants off ART for at least one month to determine eligibility, adding text for rash management; text added for withdrawal based on new rash management wording; modification of text on decline in renal function; adding syphilis screening, drugs of abuse (including alcohol) screening, and serum cetaminophen test to liver event follow-up assessments; adding possible Week 24 group-sequential analysis; clarification regarding MSDF algorithm; change for hepatitis B and C serology collection at Screening vs current Day 1 collection; allow co-administration of fosamprenavir with investigational products; unknown impact on efficacy if multivitamin / iron supplements are used with other medications that may decrease GSK1349572 exposure; and adding exceptions to Child Pugh Classificaton for anticoagulation therapy and use of atazanavir in failing background therapy; and updated section on publication of study results
    09 Sep 2011
    Amendment 5: This amendment is implemented to correct a formatting error in the Inclusion Criteria (Inclusion criteria #4 was incorrectly split into #4 and #5 when Amendment 04 was published); a couple minor clarifications are also included.
    22 Mar 2012
    Amendment 6: This amendment is implemented to update the prohibited medication information (rifabutin, pioglitazone, troglitazone, modafinil deleted; rifapentine added; text edited for glucocorticoids and immunomodulators); to allow a change in background therapy after Week 48 if required for tolerability/toxicity management; to allow the use of telbivudine for hepatitis B treatment; to add guidance for eCRF collection for missing visits and for reporting participants as lost to follow-up; to allow the use of pill boxes for up to 7 days; to provide clarification of when repeat PK samples should be collected for Week 24 and Week 48; and to inform that a group-sequential analysis is no longer planned for the study. Details regarding the medical monitor are also added. There is also a minor clarification regarding drug formulation and correction of a typographical error
    09 Oct 2012
    Amendment 7: Country Specific Amendment for South Africa
    21 Feb 2013
    Amendment 8: This amendment was implemented to allow GSK1349572 50 mg twice daily dosing for participants receiving efavirenz, tipranavir/ritonavir, rifampin, or rifapentine; updated drug drug interaction section; rifampin and rifapentine were also removed from the prohibited medication listing; abbreviation listing and references updated.
    19 May 2015
    Amendment 9: Country Specific Amendment for South Africa
    10 Jul 2018
    Amendment 10: Changes were made to the protocol to manage and mitigate risks following identification of a potential safety issue related to neural tube defect in infants born to women with exposure to dolutegravir at the time of conception. The Risk Assessment table was updated to include language regarding risk and mitigation of neural tube defects.Inclusion criterion #2 was updated to exclude the double barrier method of contraception, which does not meet updated GSK/ViiV criteria for a highly effective method. The withdrawal criteria were updated to include a reminder that females of reproductive potential who change their minds and desire to be pregnant, or who state they no longer are willing to comply with the approved pregnancy avoidance methods, should also be withdrawn from the study. The Time and Events table was updated to include a reminder for investigators to check at every visit that females of reproductive potential are avoiding pregnancy. Administrative updates were made.

    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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