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    Clinical Trial Results:
    A Phase III study to demonstrate the antiviral activity and safety of dolutegravir in HIV-1 infected adult subjects with treatment failure on an integrase inhibitor containing regimen.

    Summary
    EudraCT number
    		 2009-017951-87
    Trial protocol
    		 BE   PT   IT   ES  
    Global end of trial date
    25 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2016
    First version publication date
    12 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    112574
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, +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?
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this trial is to assess the antiviral activity and safety of a dolutegravir (DTG) containing regimen in HIV-1 infected, antiretroviral therapy (ART)-experienced adults with current or historical failure on an integrase inhibitor (INI) containing regimen. The study will assess DTG 50mg twice daily administered initially with the current failing ART regimen but then with an optimised background ART regimen (OBR) after Day 7. The first analyses will be conducted after the last subject enrolled has completed 24 weeks. Subjects may remain on study after Week 24.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United States: 99
    Worldwide total number of subjects
    183
    EEA total number of subjects
    81
    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)
    179
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants (par.) having documented Human immunodeficiency virus type 1 (HIV-1) infection with a plasma HIV-1 Ribonucleic acid(RNA) >=500 copies per milliliter (c/mL) at Screening, Antiretroviral therapy (ART)-experienced and on stable ART for at least one month prior to Screening were enrolled

    Pre-assignment
    Screening details
    		 A total of 139 par. were screen failures and 183 par. entered the single arm, open-label study.

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

    Arms
    Arm title
    		 Dolutegravir 50 mg BID
    Arm description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) twice a day (BID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dolutegravir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 X 50mg tablet twice daily, Tablet for oral use

    Number of subjects in period 1
    		Dolutegravir 50 mg BID
    Started
    183
    Completed
    126
    Not completed
    57
         Consent withdrawn by subject
    7
         Physician decision
    2
         Adverse event, non-fatal
    7
         Lost to follow-up
    7
         Lack of efficacy
    27
         Protocol deviation
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 183 183
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 48 (19 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 42 42
        Male
    		 141 141
    Race
    Units: Subjects
        African American/African Heritage
    		 49 49
        American Indian or Alaska Native and White
    		 1 1
        Asian-Central/South Asian Heritage
    		 1 1
        White
    		 130 130
        White and African American/African Heritage
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Dolutegravir 50 mg BID
    Reporting group description
    		 Participants received dolutegravir (DTG) 50 milligrams (mg) twice a day (BID).

    Primary: Mean change from Baseline in Plasma HIV-1 RNA at Day 8

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    End point title
    		 Mean change from Baseline in Plasma HIV-1 RNA at Day 8 [1]
    End point description
    Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8. The P-value (< 0.001) was derived by the null hypothesis testing of no change from Baseline in HIV-1 RNA at Day 8 at the two-sided 5% significance level using a single sample 2 sided, t-test. Change from baseline (-1.432) and 2 sided 95% confidence interval (-1.520 to -1.343) was calculated using T distribution. Intent-to-Treat-Exposed (ITT-E) Population is defined as all participants who received at least one dose of study drug. Only participants who had Day 8 observations were considered for analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Day 8
    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
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    182 [2]
    Units: log10 copies/milliliter (mL)
        arithmetic mean (standard deviation)
    -1.432 ± 0.607
    Notes
    [2] - Intent-to-treat-Exposed Population. One participant did not have a Day 8 visit.
    No statistical analyses for this end point

    Primary: Number of participants with HIV-1 RNA less than 50 copies (c)/mL at Week 24

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    End point title
    		 Number of participants with HIV-1 RNA less than 50 copies (c)/mL at Week 24 [3]
    End point description
    The number of par. who had viral load <50 c/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all par. without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as par. who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window. The percentage of par. with HIV-1 RNA <50 c/mL at week 24 was 69% with 2 sided 95% CI as 62% to 76%.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [4]
    Units: participants
        number (not applicable)
    126
    Notes
    [4] - ITT-E Population
    No statistical analyses for this end point

    Primary: Number of participants with HIV-1 RNA less than 50 copies(c)/mL at Week 48

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    End point title
    		 Number of participants with HIV-1 RNA less than 50 copies(c)/mL at Week 48 [5]
    End point description
    The number of participants who had viral load <50 c/mL at Week 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the VOI (due to missing data/discontinuation of investigational product prior to the visit window) as non responders, as well as participants who switched their concomitant ART prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window. The percentage of participants with HIV-1 RNA <50 c/mL at Week 48 was 63% with 2 sided 95% CI as 56% to 70%.
    End point type
    Primary
    End point timeframe
    Week 48
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [6]
    Units: participants
        number (not applicable)
    116
    Notes
    [6] - ITT-E Population
    No statistical analyses for this end point

    Primary: Number of participants with any Adverse Event (AE) or any serious adverse event (SAE)

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    End point title
    		 Number of participants with any Adverse Event (AE) or any serious adverse event (SAE) [7]
    End point description
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    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
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [8]
    Units: participants
    number (not applicable)
        Any AE
    169
        Any SAE
    46
    Notes
    [8] - Safety Population: all participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Primary: Number of participants with Adverse Events of the indicated severity, per the Division of Acquired Immune Deficiency Syndrome (DAIDS) grading scale

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    End point title
    		 Number of participants with Adverse Events of the indicated severity, per the Division of Acquired Immune Deficiency Syndrome (DAIDS) grading scale [9]
    End point description
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [10]
    Units: participants
    number (not applicable)
        Grade 1
    45
        Grade 2
    64
        Grade 3
    44
        Grade 4
    16
    Notes
    [10] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with the maximum post-Baseline-emergent clinical chemistry toxicities of the indicated grade

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    End point title
    		 Number of participants with the maximum post-Baseline-emergent clinical chemistry toxicities of the indicated grade [11]
    End point description
    The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [12]
    Units: participants
    number (not applicable)
        Grade 1
    49
        Grade 2
    67
        Grade 3
    43
        Grade 4
    16
    Notes
    [12] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with the maximum post-Baseline-emergent hematology toxicities of the indicated grade

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    End point title
    		 Number of participants with the maximum post-Baseline-emergent hematology toxicities of the indicated grade [13]
    End point description
    The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
    End point type
    Primary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [14]
    Units: Participants
    number (not applicable)
        Grade 1
    31
        Grade 2
    15
        Grade 3
    4
        Grade 4
    2
    Notes
    [14] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with plasma HIV-1 RNA less than 400 and 50 copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48

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    End point title
    		 Number of participants with plasma HIV-1 RNA less than 400 and 50 copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point description
    The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40 and 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window
    End point type
    Secondary
    End point timeframe
    Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [15]
    Units: participants
    number (not applicable)
        HIV-1 RNA <50 c/mL, Baseline
    1
        HIV-1 RNA <50 c/mL, Day 8
    28
        HIV-1 RNA <50 c/mL, Week 4
    98
        HIV-1 RNA <50 c/mL, Week 8
    112
        HIV-1 RNA <50 c/mL, Week 12
    116
        HIV-1 RNA <50 c/mL, Week 16
    116
        HIV-1 RNA <50 c/mL, Week 24
    126
        HIV-1 RNA <50 c/mL, Week 32
    117
        HIV-1 RNA <50 c/mL, Week 40
    108
        HIV-1 RNA <50 c/mL, Week 48
    116
        HIV-1 RNA <400 c/mL, Baseline
    8
        HIV-1 RNA <400 c/mL, Day 8
    82
        HIV-1 RNA <400 c/mL, Week 4
    145
        HIV-1 RNA <400 c/mL, Week 8
    146
        HIV-1 RNA <400 c/mL, Week 12
    142
        HIV-1 RNA <400 c/mL, Week 16
    139
        HIV-1 RNA <400 c/mL, Week 24
    135
        HIV-1 RNA <400 c/mL, Week 32
    127
        HIV-1 RNA <400 c/mL, Week 40
    119
        HIV-1 RNA <400 c/mL, Week 48
    125
    Notes
    [15] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with plasma HIV-1 RNA less than 400 and 50 copies/mL from Week 48 every 12 weeks up to study completion

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    End point title
    		 Number of participants with plasma HIV-1 RNA less than 400 and 50 copies/mL from Week 48 every 12 weeks up to study completion
    End point description
    The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Weeks 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Intention to treat-Exposed (ITT-E) population was defined as only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.
    End point type
    Secondary
    End point timeframe
    From Week 48 every 12 weeks up to study completion.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [16]
    Units: Participants
    number (not applicable)
        HIV-1 RNA <50 c/mL, Week 48, n =146
    121
        HIV-1 RNA <50 c/mL, Week 60, n=142
    110
        HIV-1 RNA <50 c/mL, Week 72, n=138
    116
        HIV-1 RNA <50 c/mL, Week 84, n=138
    108
        HIV-1 RNA <50 c/mL, Week 96, n=120
    101
        HIV-1 RNA <50 c/mL, Week 108, n=98
    81
        HIV-1 RNA <50 c/mL, Week 120, n=82
    72
        HIV-1 RNA <50 c/mL, Week 132, n=61
    49
        HIV-1 RNA <50 c/mL, Week 144, n=45
    37
        HIV-1 RNA <50 c/mL, Week 156, n=32
    28
        HIV-1 RNA <50 c/mL, Week 168, n=24
    20
        HIV-1 RNA <50 c/mL, Week 180, n=6
    4
        HIV-1 RNA <400 c/mL, Week 48, n=146
    134
        HIV-1 RNA <400 c/mL, Week 60, n=142
    131
        HIV-1 RNA <400 c/mL, Week 72, n=138
    130
        HIV-1 RNA <400 c/mL, Week 84, n=138
    127
        HIV-1 RNA <400 c/mL, Week 96, n=120
    111
        HIV-1 RNA <400 c/mL, Week 108, n=98
    92
        HIV-1 RNA <400 c/mL, Week 120, n=82
    80
        HIV-1 RNA <400 c/mL, Week 132, n=61
    59
        HIV-1 RNA <400 c/mL, Week 144, n=45
    44
        HIV-1 RNA <400 c/mL, Week 156, n=32
    31
        HIV-1 RNA <400 c/mL, Week 168, n=24
    23
        HIV-1 RNA <400 c/mL, Week 180, n=6
    5
    Notes
    [16] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and from Week 48 every 12 weeks up to study completion

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    End point title
    		 Mean change from Baseline in plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and from Week 48 every 12 weeks up to study completion
    End point description
    Mean change from Baseline in plasma HIV-1 RNA was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48 , 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Intention to treat-Exposed (ITT-E) population was defined as only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study completion (Up to Week 180)
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [17]
    Units: Log10 copies/mL
    arithmetic mean (standard deviation)
        Day 8, n=182
    -1.432 ± 0.607
        Week 4, n=180
    -2.088 ± 0.885
        Week 8, n=179
    -2.101 ± 0.987
        Week 12, n=174
    -2.113 ± 1.069
        Week 16, n=165
    -2.216 ± 1.005
        Week 24, n=164
    -2.211 ± 1.023
        Week 32, n=146
    -2.373 ± 0.926
        Week 40, n=144
    -2.301 ± 0.955
        Week 48, n=146
    -2.321 ± 0.981
        Week 60, n=142
    -2.356 ± 0.928
        Week 72, n=138
    -2.39 ± 0.941
        Week 84, n=138
    -2.311 ± 0.996
        Week 96, n=120
    -2.346 ± 1.008
        Week 108, n=98
    -2.394 ± 0.966
        Week 120, n=82
    -2.515 ± 0.904
        Week 132, n=61
    -2.456 ± 0.988
        Week 144, n=45
    -2.585 ± 0.983
        Week 156, n=32
    -2.595 ± 1.009
        Week 168, n=24
    -2.719 ± 0.898
        Week 180, n=6
    -2.425 ± 1.557
    Notes
    [17] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Absolute values for CD4+ cell counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ cell counts at Baseline and Weeks 4, 12, 24, and 48

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    End point title
    		 Absolute values for CD4+ cell counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ cell counts at Baseline and Weeks 4, 12, 24, and 48
    End point description
    Absolute values for CD4+ cell counts were assessed at Baseline, Day 8 and Weeks 4, 8, 12, 16, and 24, and absolute values for CD8+ cell counts were assessed at Baseline and Weeks 4, 12, 24, and 48. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [18]
    Units: Cells per millimeters cubed (cells/mm^3)
    median (inter-quartile range (Q1-Q3))
        CD4+, Baseline, n=183
    140 (40 to 330)
        CD4+, Day 8, n=181
    170 (60 to 350)
        CD4+, Week 4, n=178
    185 (80 to 350)
        CD4+, Week 8, n=178
    210 (100 to 350)
        CD4+, Week 12, n=171
    210 (110 to 360)
        CD4+, Week 16, n=165
    210 (130 to 400)
        CD4+, Week 24, n=163
    250 (130 to 420)
        CD4+, Week 32, n=147
    270 (170 to 440)
        CD4+, Week 40, n=143
    290 (200 to 440)
        CD4+, Week 48, n=145
    310 (200 to 450)
        CD8+, Week 4, n=181
    860 (540 to 1220)
        CD8+, Week 4, n=176
    970 (655 to 1405)
        CD8+, Week 12, n=170
    1015 (730 to 1460)
        CD8+, Week 24, n=154
    1020 (690 to 1460)
        CD8+, Week 48, n=140
    1000 (720 to 1380)
    Notes
    [18] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Median change from Baseline in CD4+ cell counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and from Week 48 every 12 weeks until study completion

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    End point title
    		 Median change from Baseline in CD4+ cell counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and from Week 48 every 12 weeks until study completion
    End point description
    Median change from Baseline in CD4+ cell counts was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180.
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [19]
    Units: Cells per millimeters cubed (cells/mm^3)
    median (inter-quartile range (Q1-Q3))
        CD4+, Day 8, n=181
    20 (0 to 60)
        CD4+, Week 4, n=178
    30 (0 to 71)
        CD4+, Week 8, n=178
    40 (0 to 81)
        CD4+, Week 12, n=171
    50 (0 to 100)
        CD4+, Week 16, n=165
    60 (20 to 130)
        CD4+, Week 24, n=163
    61 (20 to 130)
        CD4+, Week 32, n=147
    100 (20 to 160)
        CD4+, Week 40, n=143
    90 (30 to 180)
        CD4+, Week 48, n=145
    110 (40 to 190)
        CD4+, Week 60, n=142
    120 (50 to 210)
        CD4+, Week 72, n=138
    140 (60 to 231)
        CD4+, Week 84, n=137
    150 (80 to 240)
        CD4+, Week 96, n=117
    160 (80 to 270)
        CD4+, Week 108, n=98
    180.5 (80 to 280)
        CD4+, Week 120, n=82
    180 (100 to 280)
        CD4+, Week 132, n=61
    221 (100 to 320)
        CD4+, Week 144, n=46
    205 (130 to 350)
        CD4+, Week 156, n=32
    225 (155 to 345)
        CD4+, Week168, n=24
    265 (155 to 380)
        CD4+, Week180, n=6
    170.5 (140 to 230)
    Notes
    [19] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Ratio of CD4+/CD8+ cell count at Baseline and Weeks 4, 12, 24, and 48

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    End point title
    		 Ratio of CD4+/CD8+ cell count at Baseline and Weeks 4, 12, 24, and 48
    End point description
    The ratio of CD4+/CD8+ cell count (measured in cells/mm^3) was assessed at Baseline and at Weeks 4, 12, 24, and 48. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count. Only those participants with data available at the indicated time points were considered for analysis (represented by n=X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the ITT-E Population.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 12, 24, and 48
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [20]
    Units: ratio
    median (inter-quartile range (Q1-Q3))
        Baseline, n=180
    0.15 (0.05 to 0.34)
        Week 4, n=176
    0.19 (0.09 to 0.37)
        Week 12, n=170
    0.21 (0.1 to 0.46)
        Week 24, n=154
    0.26 (0.14 to 0.46)
        Week 48, n=140
    0.32 (0.19 to 0.52)
    Notes
    [20] - ITT-E population
    No statistical analyses for this end point

    Secondary: Number of participants with HIV-1 disease progression (Acquired Immune Deficiency Syndrome [AIDS] or death)

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    End point title
    		 Number of participants with HIV-1 disease progression (Acquired Immune Deficiency Syndrome [AIDS] or death)
    End point description
    The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).
    End point type
    Secondary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [21]
    Units: Participants
    number (not applicable)
        Progression from CDC Class A to Class C Event
    1
        Progression from CDC Class B to Class C Event
    2
        Progression from CDC Class C to New Class C Event
    6
        Progression from Classes A, B, or C to Death
    2
    Notes
    [21] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Cmax and Ctau of DTG

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    End point title
    		 Cmax and Ctau of DTG
    End point description
    The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24. The Pharmacokinetic (PK) Concentration Population used is defined as all subjects who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.
    End point type
    Secondary
    End point timeframe
    Day 8, Week 4, and Week 24
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [22]
    Units: Micrograms per milliliter (µg/mL)
    geometric mean (confidence interval 95%)
        Cmax
    4.74 (4.18 to 5.36)
        Ctau
    2.6 (2.15 to 3.15)
    Notes
    [22] - The Pharmacokinetic (PK) Concentration Population
    No statistical analyses for this end point

    Secondary: AUC(0-tau) and AUC(0-24) of DTG

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    End point title
    		 AUC(0-tau) and AUC(0-24) of DTG
    End point description
    The area under the time concentration curve over the dosing interval (AUC[0-tau]) and from 0 to 24 hours (AUC[0-24]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24. The Pharmacokinetic (PK) Concentration Population used is defined as all subjects who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.
    End point type
    Secondary
    End point timeframe
    Day 8, Week 4, and Week 24
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    183 [23]
    Units: µg*hour/mL
    geometric mean (confidence interval 95%)
        AUC(0-tau)
    36.7 (35 to 38.6)
        AUC(0-24)
    73.5 (70 to 77.1)
    Notes
    [23] - The Pharmacokinetic (PK) Concentration Population
    No statistical analyses for this end point

    Secondary: C0 assessment of DTG

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    End point title
    		 C0 assessment of DTG
    End point description
    The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hours post-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population. The Pharmacokinetic (PK) Concentration Population used is defined as all subjects who received DTG, had undergone PK sampling during the study, and provided evaluable DTG plasma concentration data.
    End point type
    Secondary
    End point timeframe
    Day 8, Week 4, and Week 24
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    161 [24]
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Day 8, n=148
    2.36 ± 91
        Week 4, n=161
    1.9 ± 113
        Week 24, n=135
    2.14 ± 93
    Notes
    [24] - Pharmacokinetic (PK) Parameter Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated treatment-emergent integrase (IN) mutations detected at the time of protocol-defined virologic failure (PDVF) as a measure of genotypic resistance

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    End point title
    		 Number of participants with the indicated treatment-emergent integrase (IN) mutations detected at the time of protocol-defined virologic failure (PDVF) as a measure of genotypic resistance
    End point description
    Analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is a <0.5 log10 c/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 c/mL. PDVF after Day 8 is defined as virological non-responses (decrease in plasma HIV-1 RNA of <1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 c/mL and confirmed plasma HIV-1 RNA levels >=400 c/mL on or after Week 24) & virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 c/mL after prior confirmed suppression to <400 c/mL & confirmed plasma HIV-1 RNA levels >1 log10 c/mL above the nadir value [nadir: >=400 c/mL]). PDVF Genotypic Resistance (GR) populations: all par. in the ITT-E Population with available on-treatment GR data at the time of PDVF. Only par. with baseline IN mutations with PDVF who had paired baseline and time of PDVF samples considered.
    End point type
    Secondary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    42 [25]
    Units: participants
    number (not applicable)
        Any IN mutation
    25
        T97A
    8
        T97T/A
    4
        E138A
    1
        E138E/A
    1
        E138E/K
    3
        E138K
    4
        E138T/A
    1
        N155H
    6
        N155N/H
    1
        Q148H
    3
        Q148Q/H
    2
        Q148R
    1
        Q148Q/R/K
    1
        G140G/S
    1
        G140S
    3
        L74L/M/V
    1
        L74L/M
    1
        L74I
    1
        E92E/Q
    2
        S147G
    2
        E157E/Q
    1
        V151V/M/I
    1
        Y143Y/H
    1
    Notes
    [25] - PDVF Genotypic Resistance Populations
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated fold increase in DTG FC (fold change in IC50 [50% inhibitory concentration] relative to wild-type virus) between Baseline and the time of PDVF, as a measure of post-Baseline phenotypic resistance

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    End point title
    		 Number of participants with the indicated fold increase in DTG FC (fold change in IC50 [50% inhibitory concentration] relative to wild-type virus) between Baseline and the time of PDVF, as a measure of post-Baseline phenotypic resistance
    End point description
    The FC in IC50 for DTG relative to wild-type virus was determined for virus isolated at Baseline & at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined as a <0.5 log10 c/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 c/mL. PDVF after Day 8 was defined for virological non-response (decrease in plasma HIV-1 RNA of less than 1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 c/mL and confirmed plasma HIV-1 RNA levels >=400 c/mL on or after Week 24) & virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 c/mL after prior confirmed suppression to <400 c/mL and confirmed plasma HIV-1 RNA levels >1 log10 c/mL above the nadir value, where nadir is >=400 c/mL). PDVF Phenotypic Resistance Populations are the only par. with Baseline DTG IC50 with PDVF who had paired Baseline & time of virological failure are considered.
    End point type
    Secondary
    End point timeframe
    From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
    End point values
    		 Dolutegravir 50 mg BID
    Number of subjects analysed
    45 [26]
    Units: Participants
    number (not applicable)
        <1 fold
    6
        1-<2 fold
    16
        2-<4 fold
    4
        4-<8 fold
    4
        >=8 fold
    12
        Missing
    3
    Notes
    [26] - PDVF Phenotypic Resistance Populations.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from start of study treament until the end of treatment visit for each participant (up to Week 180)
    Adverse event reporting additional description
    On-treatment SAEs and non-serious AEs were reported for the Safety population consisted of all participants who received at least one dose of investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Dolutegravir 50 mg BID
    Reporting group description
    		 Participants received DTG 50 mg BID.

    Serious adverse events
    		 Dolutegravir 50 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 183 (25.14%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anogenital warts
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hodgkin's disease recurrent
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal cancer stage I
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lip and/or oral cavity cancer stage 0
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian mass
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nodular regenerative hyperplasia
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tendonitis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint destruction
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 183 (2.73%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes ophthalmic
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye infection toxoplasmal
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dolutegravir 50 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    143 / 183 (78.14%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 183 (6.01%)
         occurrences all number
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 183 (13.11%)
         occurrences all number
    27
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 183 (9.29%)
         occurrences all number
    17
    Pyrexia
         subjects affected / exposed
    19 / 183 (10.38%)
         occurrences all number
    25
    Asthenia
         subjects affected / exposed
    13 / 183 (7.10%)
         occurrences all number
    17
    Injection site reaction
         subjects affected / exposed
    12 / 183 (6.56%)
         occurrences all number
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    41 / 183 (22.40%)
         occurrences all number
    53
    Nausea
         subjects affected / exposed
    26 / 183 (14.21%)
         occurrences all number
    29
    Vomiting
         subjects affected / exposed
    13 / 183 (7.10%)
         occurrences all number
    13
    Abdominal pain upper
         subjects affected / exposed
    14 / 183 (7.65%)
         occurrences all number
    14
    Constipation
         subjects affected / exposed
    12 / 183 (6.56%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    29 / 183 (15.85%)
         occurrences all number
    36
    Oropharyngeal pain
         subjects affected / exposed
    10 / 183 (5.46%)
         occurrences all number
    10
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    17 / 183 (9.29%)
         occurrences all number
    19
    Pruritus
         subjects affected / exposed
    11 / 183 (6.01%)
         occurrences all number
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 183 (7.65%)
         occurrences all number
    15
    Anxiety
         subjects affected / exposed
    10 / 183 (5.46%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    18 / 183 (9.84%)
         occurrences all number
    22
    Arthralgia
         subjects affected / exposed
    12 / 183 (6.56%)
         occurrences all number
    17
    Pain in extremity
         subjects affected / exposed
    11 / 183 (6.01%)
         occurrences all number
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    25 / 183 (13.66%)
         occurrences all number
    35
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 183 (12.02%)
         occurrences all number
    25
    Nasopharyngitis
         subjects affected / exposed
    12 / 183 (6.56%)
         occurrences all number
    14
    Rhinitis
         subjects affected / exposed
    11 / 183 (6.01%)
         occurrences all number
    14
    Influenza
         subjects affected / exposed
    11 / 183 (6.01%)
         occurrences all number
    11
    Sinusitis
         subjects affected / exposed
    11 / 183 (6.01%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2011
    Clarification of statistical algorithm (MSDF), guidance on Entecavir use provided, cautionary text added to Permitted Medications and Non-Drug Therapies section, Rifapentine added to Prohibited Medications plus additional guidance, management of subjects with Decline in Renal Function amended, addition of section on Rash management, addition of ATV use to exceptions statement in Appendix 3: Child-Pugh classification, correction of typographical errors and minor edits.

    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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