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    Clinical Trial Results:
    A Phase IIb pilot study to assess the antiviral activity of GSK1349572 containing regimen in antiretroviral therapy (ART)-experienced, HIV-1-infected adult subjects with raltegravir resistance

    Summary
    EudraCT number
    2009-010270-37
    Trial protocol
    FR   ES   IT  
    Global end of trial date
    23 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    13 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ING112961
    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, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the short-term antiviral activity of GSK1349572 + failing background regimen.
    Protection of trial subjects
    Not applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Aug 2009
    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
    Spain: 5
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    51
    EEA total number of subjects
    32
    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)
    50
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants (par.) recruited initially to Cohort I and subsequently to Cohort II. Recruitment to Cohort I was closed 9 months before recruitment to Cohort II was opened. Recruitment was not randomized.

    Pre-assignment
    Screening details
    The study will included ART-experienced participants with either current or past virologic failure to raltegravir.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort I (DTG 50 mg OD)
    Arm description
    Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).
    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
    50 mg once daily (Cohort I)

    Arm title
    Cohort II (DTG 50 mg BID)
    Arm description
    Participants received DTG 50 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
    50 mg twice daily (Cohort II)

    Number of subjects in period 1
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Started
    27
    24
    Completed
    11
    14
    Not completed
    16
    10
         Protocol deviation
    1
    1
         Adverse event, serious fatal
    3
    2
         Adverse event, non-fatal
    -
    1
         Insufficient Viral Load Response
    12
    3
         Lost to follow-up
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort I (DTG 50 mg OD)
    Reporting group description
    Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

    Reporting group title
    Cohort II (DTG 50 mg BID)
    Reporting group description
    Participants received DTG 50 mg twice a day (BID).

    Reporting group values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID) Total
    Number of subjects
    27 24 51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    48 (19 to 61) 47 (33 to 68) -
    Gender categorical
    Units: Subjects
        Female
    2 6 8
        Male
    25 18 43
    Race
    Units: Subjects
        African American/African Heritage
    3 5 8
        White-Arabic/North African Heritage
    1 1 2
        White-White/Caucasian/European Heritage
    23 18 41

    End points

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    End points reporting groups
    Reporting group title
    Cohort I (DTG 50 mg OD)
    Reporting group description
    Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

    Reporting group title
    Cohort II (DTG 50 mg BID)
    Reporting group description
    Participants received DTG 50 mg twice a day (BID).

    Primary: Number of participants who achieved HIV-1 RNA <400 copies (c)/milliliter (mL) or at least 0.7 log10 c/mL below their Baseline value at Day 11

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    End point title
    Number of participants who achieved HIV-1 RNA <400 copies (c)/milliliter (mL) or at least 0.7 log10 c/mL below their Baseline value at Day 11 [1]
    End point description
    The number of participants who achieved Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11 was assessed. The last observation was carried forward if a participant had missed the Day 11 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 11. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 11. Intent-to-Treat Exposed (ITT-E) Population: all participants who received at least one dose of study medication and who had at least one post-Baseline measure of plasma HIV-1 RNA.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Day 11
    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: Statistical information is not permitted to be entered into the system for a single arm.
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [2]
    24 [3]
    Units: Participants
    21
    23
    Notes
    [2] - ITT-E Population
    [3] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, Weeks 4, 12, 24, 48, 72, 96, from Week 108 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 6 to 8, Day 11, Weeks 4, 12, 24, 48, 72, 96, from Week 108 every 12 weeks up to study completion
    End point description
    Mean change from Baseline in Plasma HIV-1 RNA was assessed on Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 using data of the observed cases. Study Day 1 was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the indicated time points were analyzed (represented by n=X, X in the category titles). 99999 represents NA.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, 96, from 108 every 12 weeks up to study completion
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [4]
    24 [5]
    Units: Log10 copies/mL
    arithmetic mean (standard deviation)
        Day 6 to 8, n=27, 24
    -1.31 ± 0.71
    -1.4 ± 0.43
        Day 11, n= 27, 24
    -1.45 ± 0.77
    -1.76 ± 0.53
        Week 4, n= 26, 24
    -1.82 ± 1.03
    -2.06 ± 0.78
        Week 12, n= 22, 24
    -1.94 ± 1.14
    -2.3 ± 0.93
        Week 24, n= 18, 22
    -1.99 ± 1.08
    -2.5 ± 0.81
        Week 48, n= 15, 20
    -2.02 ± 1.07
    -2.63 ± 0.78
        Week 72, n= 14, 18
    -2.1 ± 1.03
    -2.71 ± 0.82
        Week 96, n= 13, 15
    -2.06 ± 1.13
    -2.58 ± 0.77
        Week 108, n= 13, 17
    -1.95 ± 1.2
    -2.69 ± 0.82
        Week 120, n= 11, 17
    -2.09 ± 1.15
    -2.67 ± 0.85
        Week 132, n= 11, 17
    -1.83 ± 1.01
    -2.66 ± 0.86
        Week 144, n= 12, 15
    -2.08 ± 1.29
    -2.62 ± 0.94
        Week 156, n= 12, 15
    -2.04 ± 1.36
    -2.65 ± 0.77
        Week 168, n= 11, 14
    -1.77 ± 1.26
    -2.72 ± 0.89
        Week 180, n= 11, 10
    -1.76 ± 1.11
    -2.56 ± 0.82
        Week 192, n= 9, 7
    -1.87 ± 1.16
    -2.51 ± 0.98
        Week 204, n= 10, 6
    -1.76 ± 1.21
    -2.35 ± 0.71
        Week 216, n= 9, 6
    -1.61 ± 1.08
    -2.35 ± 0.71
        Week 228, n= 6, 4
    -1.79 ± 1.08
    -2.33 ± 0.9
        Week 240, n= 7, 0
    -1.63 ± 1.13
    99999 ± 99999
        Week 252, n= 4, 0
    -1.72 ± 1.07
    99999 ± 99999
        Week 264, n= 1, 0
    -2.9 ± 99999
    99999 ± 99999
    Notes
    [4] - ITT-E Population
    [5] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants who achieved plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR analysis.

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    End point title
    Number of participants who achieved plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR analysis.
    End point description
    The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 4, 12, 24, 48, 72, and 96 per the Food and Drug Administration's Time to Loss of Virological Response (TLOVR) algorithm. Using the TLOVR algorithm, participants are considered to have failed on therapy if they never achieved confirmed RNA levels below the threshold, if they had confirmed rebound of RNA above the threshold, if they made a non-permitted change in background regimen, or if they permanently discontinued investigational product for any reason. 99999 represents NA.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 4, 12, 24, 48, 72, and 96
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [6]
    24 [7]
    Units: Participants
        Baseline, <50 c/mL
    0
    0
        Week 4, <50 c/mL
    9
    12
        Week 12, <50 c/mL
    13
    16
        Week 24, <50 c/mL
    11
    19
        Week 48, <50 c/mL
    9
    17
        Week 72, <50 c/mL
    8
    99999
        Week 96, <50 c/mL
    7
    99999
        Baseline, <400 c/mL
    0
    0
        Week 4, <400 c/mL
    16
    17
        Week 12, <400 c/mL
    16
    20
        Week 24, <400 c/mL
    14
    20
        Week 48, <400 c/mL
    13
    18
        Week 72, <400 c/mL
    12
    99999
        Week 96, <400 c/mL
    10
    99999
    Notes
    [6] - ITT-E Population
    [7] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Proportion of participants who achieved plasma HIV-1 RNA <400 c/mL and <50 c/mL from Week 48 every 12 weeks up to study completion

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    End point title
    Proportion of participants who achieved plasma HIV-1 RNA <400 c/mL and <50 c/mL from Week 48 every 12 weeks up to study completion
    End point description
    The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). 99999 represents NA.
    End point type
    Secondary
    End point timeframe
    From Week 48 every 12 weeks up to study completion
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [8]
    24 [9]
    Units: Percentage of Participants
        Week 48, <50 c/mL, n=15, 20
    60
    80
        Week 60, <50 c/mL, n=13, 18
    69
    94
        Week 72, <50 c/mL, n=14, 18
    64
    78
        Week 84, <50 c/mL, n=14, 18
    57
    78
        Week 96, <50 c/mL, n=13, 15
    54
    87
        Week 108, <50 c/mL, n=13, 17
    54
    88
        Week 120, <50 c/mL, n=11, 17
    55
    88
        Week 132, <50 c/mL, n=11, 17
    55
    82
        Week 144, <50 c/mL, n=12, 15
    58
    87
        Week 156, <50 c/mL, n=12, 15
    67
    93
        Week 168, <50 c/mL, n=11, 14
    64
    86
        Week 180, <50 c/mL, n=11, 10
    64
    100
        Week 192, <50 c/mL, n= 9, 7
    67
    100
        Week 204, <50 c/mL, n= 10, 6
    50
    100
        Week 216, <50 c/mL, n= 9, 6
    56
    100
        Week 228, <50 c/mL, n=6, 4
    67
    100
        Week 240, <50 c/mL, n=7,0
    57
    99999
        Week 252, <50 c/mL, n=4, 0
    50
    99999
        Week 264, <50 c/mL, n=1, 0
    100
    99999
        Week 48, <400 c/mL, n=15, 20
    73
    95
        Week 60,<400 c/mL, n=13, 18
    92
    100
        Week 72,<400 c/mL, n=14, 18
    79
    100
        Week 84,<400 c/mL, n=14, 18
    71
    94
        Week 96,<400 c/mL, n=13, 15
    85
    100
        Week 108, <400 c/mL, n=13,17
    85
    100
        Week 120,<400 c/mL, n=11, 17
    82
    94
        Week 132,<400 c/mL, n=11,17
    82
    94
        Week 144,<400 c/mL, n=12, 15
    83
    93
        Week 156,<400 c/mL, n=12, 15
    75
    100
        Week 168,<400 c/mL, n=11, 14
    82
    100
        Week 180,<400 c/mL, n=11, 10
    73
    100
        Week 192,<400 c/mL, n=9, 7
    78
    100
        Week 204,<400 c/mL, n=10, 6
    70
    100
        Week 216,<400 c/mL, n=9, 6
    56
    100
        Week 228, <400 c/mL, n=6, 4
    67
    100
        Week 240, <400 c/mL, n=7, 0
    71
    99999
        Week 252, <400 c/mL, n=4, 0
    50
    99999
        Week 264, <400 c/mL, n=1, 0
    100
    99999
    Notes
    [8] - ITT-E Population
    [9] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Change from baseline in CD4+ cell count at Day 11 and Weeks 4, 12, 24, 48, 72, 96, Week 108 every 12 weeks up to study completion

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    End point title
    Change from baseline in CD4+ cell count at Day 11 and Weeks 4, 12, 24, 48, 72, 96, Week 108 every 12 weeks up to study completion
    End point description
    Change from Baseline in CD4+ cell count was assessed at Day 11 and at Weeks 4, 12, 24, 48, 72, 96,108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264. Study Day 1 was considered as Baseline.Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the indicated time points were analyzed (represented by n=X, X in the category titles). 99999 represents NA.
    End point type
    Secondary
    End point timeframe
    Baseline; Day 11; Weeks 4, 12, 24, 48, 72, 96, from 108 every 12 weeks up to study completion
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [10]
    24 [11]
    Units: cells per cubic millimeter (mm^3)
    median (inter-quartile range (Q1-Q3))
        Baseline, n=27, 24
    114 (44 to 227)
    202 (19 to 384)
        Day 11, n=27, 24
    34 (2 to 71)
    14 (0 to 69)
        Week 4, n=27, 24
    57 (33 to 108)
    35 (8 to 69)
        Week 12, n= 22, 24
    84 (26 to 124)
    57 (8 to 103)
        Week 24, n=17, 22
    78 (54 to 175)
    79 (17 to 147)
        Week 48, n=15, 20
    102 (29 to 160)
    106 (45 to 245)
        Week 72, n=14, 18
    163 (58 to 204)
    191.5 (80 to 277)
        Week 96, n=13, 15
    142 (75 to 202)
    189 (75 to 280)
        Week 108, n=13, 17
    124 (68 to 249)
    155 (91 to 276)
        Week 120, n=11, 17
    221 (62 to 306)
    221 (135 to 314)
        Week 132, n=11, 17
    97 (26 to 303)
    158 (129 to 384)
        Week 144, n=12, 15
    121 (28 to 284)
    278 (113 to 340)
        Week 156, n=12, 15
    212 (64 to 378)
    223 (131 to 309)
        Week 168, n=11, 13
    97 (-102 to 365)
    271 (93 to 357)
        Week 180, n=11, 10
    125 (55 to 327)
    224 (163 to 288)
        Week 192, n=10, 7
    94 (61 to 291)
    343 (304 to 429)
        Week 204, n=10, 6
    92 (47 to 364)
    264 (186 to 370)
        Week 216, n=9, 6
    172 (48 to 416)
    252 (147 to 421)
        Week 228, n=7, 3
    148 (66 to 357)
    417 (-12 to 633)
        Week 240, n=7, 0
    158 (119 to 470)
    99999 (99999 to 99999)
        Week 252, n=4, 0
    157 (109 to 282)
    99999 (99999 to 99999)
        Week 264, n=1, 0
    560 (560 to 560)
    99999 (99999 to 99999)
    Notes
    [10] - ITT-E Population
    [11] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Cmax, Cmin, and Ctau of DTG

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    End point title
    Cmax, Cmin, and Ctau of DTG
    End point description
    The maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), and concentration at the end of a dosing interval (Ctau) of DTG were assessed at Day 10. Blood samples for pharmacokinetic (PK) assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID. Pharmacokinetic (PK) Parameter Population: all participants who provided at least one evaluable PK concentration.
    End point type
    Secondary
    End point timeframe
    Day 10
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    25 [12]
    23 [13]
    Units: Micrograms per milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        Cmax
    3.04 ± 38
    5.41 ± 40
        Ctau
    0.69 ± 91
    2.72 ± 70
        Cmin
    0.48 ± 136
    2.61 ± 67
    Notes
    [12] - PK Parameter Population
    [13] - PK Parameter 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 10, and Weeks 4 and 24. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose).
    End point type
    Secondary
    End point timeframe
    Day 10; Weeks 4 and 24
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    25 [14]
    23 [15]
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        C0, Day 10
    0.51 ± 139
    3.2 ± 69
        C0, Week 4
    0.57 ± 100
    2.55 ± 63
        C0, Week 24
    0.38 ± 114
    2.38 ± 69
    Notes
    [14] - PK Parameter Population
    [15] - PK Parameter Population
    No statistical analyses for this end point

    Secondary: Tmax of DTG

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    End point title
    Tmax of DTG
    End point description
    The tmax is defined as the time of occurrence of the maximum plasma concentration (Cmax). The tmax was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.
    End point type
    Secondary
    End point timeframe
    Day 10
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    25 [16]
    23 [17]
    Units: Hours
        median (full range (min-max))
    2.97 (1.97 to 7.92)
    2 (0 to 7.87)
    Notes
    [16] - PK Parameter Population
    [17] - PK Parameter Population
    No statistical analyses for this end point

    Secondary: AUC0-24 assessment of DTG

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    End point title
    AUC0-24 assessment of DTG
    End point description
    AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure. AUC(0-24) is defined as the area under the concentration-time curve from time zero (pre-dose) to 24 hours. AUC0-24 of DTG was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.
    End point type
    Secondary
    End point timeframe
    Day 10
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    25 [18]
    23 [19]
    Units: Micrograms*hour per milliliter (µg*hr/mL
        geometric mean (geometric coefficient of variation)
    36.46 ± 53
    93.36 ± 50
    Notes
    [18] - PK Parameter Population
    [19] - PK Parameter Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated HIV-1 associated conditions, excluding recurrences

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    End point title
    Number of participants with the indicated HIV-1 associated conditions, excluding recurrences
    End point description
    The number of par. with post-Baseline emergent HIV-1 disease progression (Acquired immunodeficiency syndrome (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 (par. with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (par. 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). Par. may have more than one HIV associated condition. condition is counted only once
    End point type
    Secondary
    End point timeframe
    From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [20]
    24 [21]
    Units: Participants
        Category B, Candidiasis, oropharyngeal
    3
    2
        Category B, Hairy leukoplakia, oral
    2
    0
        Category B, Herpes Zoster
    2
    0
        Category C, Herpes simplex
    1
    0
        Category C, Candidiasis, esophageal
    0
    1
        Category C, Cytomegalovirus retinitis
    0
    1
        Category C, Kaposi's sarcoma
    1
    0
        Category C, Lymphoma, Burkitt's
    0
    1
        Category C, Lymphoma, immunoblastic
    1
    0
        Death, Brain mass
    1
    0
        Death, Completed suicide
    0
    1
        Death, Febrile bone marrow aplasia
    1
    0
        Death, Immunoblastic lymphoma
    1
    0
        Death, Acute pulmonary oedema
    1
    0
        Death, Anaemia
    0
    1
        Death, Haemochromatosis
    0
    1
        Death, Hepatic fibrosis
    0
    1
        Other: Cryptosporidiosis, acute intestinal
    0
    1
        Other: leukoplasia of both side of the tongue
    1
    0
    Notes
    [20] - ITT-E Population. Each condition is counted only once per participant regardless of recurrence.
    [21] - ITT-E Population. Each condition is counted only once per participant regardless of recurrence.
    No statistical analyses for this end point

    Secondary: Number of participants with HIV-1 associated disease progression with the indicated shifts to CDC Class C or death

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    End point title
    Number of participants with HIV-1 associated disease progression with the indicated shifts to CDC Class C or death
    End point description
    The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the 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 study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [22]
    24 [23]
    Units: Participants
        From CDC class A to CDC class C
    0
    2
        From CDC class B to CDC class C
    0
    2
        From CDC class C to new CDC class C
    1
    0
        From CDC Class A, B, or C to death
    3
    2
    Notes
    [22] - ITT-E Population
    [23] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants (cumulative) with protocol-defined virological failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, 96, Week 108 every 12 weeks up to study completion

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    End point title
    Number of participants (cumulative) with protocol-defined virological failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, 96, Week 108 every 12 weeks up to study completion
    End point description
    PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample. 99999 represents NA.
    End point type
    Secondary
    End point timeframe
    Day 11; Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, 96, from Week 108 every 12 weeks up to study completion
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [24]
    24 [25]
    Units: Participants
        Day 11
    6
    1
        Week 8
    7
    3
        Week 12
    9
    3
        Week 16
    10
    5
        Week 20
    10
    5
        Week 24
    12
    5
        Week 32
    12
    5
        Week 40
    12
    5
        Week 48
    13
    5
        Week 60
    13
    5
        Week 72
    14
    6
        Week 84
    15
    6
        Week 96
    16
    6
        Week 108
    16
    6
        Week 120
    16
    6
        Week 132
    16
    6
        Week 144
    16
    7
        Week 156
    16
    7
        Week 168
    16
    7
        Week 180
    16
    7
        Week 192
    16
    7
        Week 204
    16
    7
        Week 216
    17
    7
        Week 228
    18
    7
        Week 240
    18
    99999
        Week 252
    18
    99999
        Week 264
    18
    99999
    Notes
    [24] - ITT-E Population
    [25] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated genotypic resistance at Baseline

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    End point title
    Number of participants with the indicated genotypic resistance at Baseline
    End point description
    At Baseline, the integrase genotypic results were used to document resistance to raltegravir (RAL) and for the allocation of participants to one of two genotypic groups according to their RAL signature mutations to ensure a broad range of sensitivity to DTG. These results were not used to pre-define subgroup for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [26]
    24 [27]
    Units: Participants
        Q148 + 2
    3
    2
        Q 148 + 1
    4
    8
        Mixture
    2
    1
        Y143
    12
    6
        N155
    4
    6
        Other
    2
    1
    Notes
    [26] - ITT-E Population
    [27] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Median Fold change in sensitivity to DTG by the Baseline (Day 1) IN mutational group

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    End point title
    Median Fold change in sensitivity to DTG by the Baseline (Day 1) IN mutational group
    End point description
    Summary of median fold change in sensitivity to DTG by Integrase (IN) mutational group was assessed. The IN mutational group comprises of the following mutations: Q148 +2, Q148 +1, mixture (participants with virus containing more than one Y143, Q148 or N155 mutation at Day 1), Y143, N155, other (participants with virus having no mutations at codons 143, 148, or 155 at Day 1). Fold change (FC) is the fold change in 50% Inhibitory Concentration (IC50) relative to the wild-type control virus.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [28]
    24 [29]
    Units: Percentage
    median (full range (min-max))
        Q148 + 2, n=3, 2
    21 (14 to 35)
    4 (2.1 to 6)
        Q148 + 1, n=4, 8
    5.5 (3.3 to 25)
    5.5 (4.1 to 8.2)
        Mixture, n=2, 1
    7.8 (6.5 to 9.1)
    9.48 (9.48 to 9.48)
        Y143, n=12, 6
    1.1 (0.6 to 1.4)
    1.2 (0.92 to 1.8)
        N155, n=4, 6
    1.8 (1.5 to 5.1)
    2.3 (1.3 to 4)
        Other, n=2, 1
    1.2 (0.9 to 1.5)
    0.87 (0.87 to 0.87)
    Notes
    [28] - ITT-E Population
    [29] - ITT-E 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
    An 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 defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample. On-treatment Genotypic Resistance Population: all ITT-E participants who met the criteria for protocol-defined virological failure (PDVF).
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    18 [30]
    7 [31]
    Units: Participants
        Any
    11
    5
        E138T
    0
    1
        N155H
    3
    4
        T97A
    2
    0
        E92E/Q
    0
    1
        G140S
    3
    0
        L74I/M
    1
    0
        Q148H
    2
    0
        E138E/A
    1
    0
        E138E/K
    1
    2
        L74I/M/I
    1
    0
        L74M
    1
    0
        L74I
    1
    0
        T97T/A
    0
    2
        Q148R
    1
    0
        S147G
    3
    0
        E92E/V
    0
    1
        L68L/I
    1
    0
    Notes
    [30] - On-treatment Genotypic Resistance Population
    [31] - On-treatment Genotypic Resistance Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated fold increase in DTG FC (fold change in IC50 relative to wild-type virus) between Baseline (BL) 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 relative to wild-type virus) between Baseline (BL) and the time of PDVF, as a measure of post-Baseline phenotypic resistance
    End point description
    FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at BL and PDVF. Number of par. with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, ≥400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample. Only par. with both BL and PDVF time-point DTG phenotypic data were considered for analysis.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    17 [32]
    7 [33]
    Units: Participants
        <1 fold
    3
    0
        1-<2 fold
    4
    2
        2-<4 fold
    1
    0
        4-<8 fold
    1
    2
        >=8 fold
    8
    3
    Notes
    [32] - PDVF Phenotypic Resistance Population:all ITT-E par. with phenotypic resistance data at PDVF failure
    [33] - PDVF Phenotypic Resistance Population:all ITT-E par. with phenotypic resistance data at PDVF failure
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated Grade 3 and Grade 4 clinical chemistry toxicities

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    End point title
    Number of participants with the indicated Grade 3 and Grade 4 clinical chemistry toxicities
    End point description
    Hematology and clinical chemistry data were summarized according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Potentially life-threatening. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. The Grade 3 and Grade 4 clinical chemistry toxicities included: Albumin, Alkaline Phosphatase, Amylase, Aspartate Amino Transferase, Carbon dioxide content/Bicarbonate, Creatinine, Creatinine Clearance, Hypercalcemia, Hyperglycaemia, Hyperkalemia, Hypernatremia, Hypocalcemia, Hypoglycaemia, Hypokalemia, Hyponatremia, LDL Cholesterol, Magnesium, Phosphorus inorganic, aTotal Bilirubin, Alanine Amino Transferase, Calcium, Chloride, Cholesterol, Creatine Kinase, Direct Bilirubin, Glucose, High Density Lipid (HDL), Cholesterol direct, Lipase, Potassium, Sodium, Total Cholesterol, Triglycerides, Urea/Blood Urine Nitrogen.
    End point type
    Secondary
    End point timeframe
    From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [34]
    24 [35]
    Units: Participants
        Albumin, Grade 3
    0
    0
        Albumin, Grade 4
    0
    0
        Alkaline Phosphatase, Grade 3
    0
    0
        Alkaline Phosphatase, Grade 4
    0
    0
        Amylase, Grade 3
    1
    2
        Amylase, Grade 4
    1
    0
        Aspartate Amino Transferase, Grade 3
    0
    0
        Aspartate Amino Transferase, Grade 4
    0
    0
        Carbon dioxide content/Bicarbonate, Grade 3
    0
    0
        Carbon dioxide content/Bicarbonate, Grade 4
    0
    0
        Creatinine, Grade 3
    0
    0
        Creatinine, Grade 4
    0
    0
        Creatinine Clearance, estimated, Grade 3
    0
    0
        Creatinine Clearance, estimated, Grade 4
    0
    0
        Hypercalcemia, Grade 3
    0
    0
        Hypercalcemia, Grade 4
    0
    0
        Hyperglycaemia, Grade 3
    0
    0
        Hyperglycaemia, Grade 4
    0
    0
        Hyperkalemia, Grade 3
    0
    0
        Hyperkalemia, Grade 4
    0
    0
        Hypernatremia, Grade 3
    1
    0
        Hypernatremia, Grade 4
    0
    0
        Hypocalcemia, Grade 3
    0
    0
        Hypocalcemia, Grade 4
    0
    0
        Hypoglycaemia, Grade 3
    1
    0
        Hypoglycaemia, Grade 4
    0
    1
        Hypokalemia, Grade 3
    0
    0
        Hypokalemia, Grade 4
    0
    0
        Hyponatremia, Grade 3
    0
    0
        Hyponatremia, Grade 4
    0
    0
        LDL Cholesterol, Grade 3
    2
    1
        LDL Cholesterol, Grade 4
    0
    0
        Magnesium, Grade 3
    0
    0
        Magnesium, Grade 4
    0
    0
        Phosphorus inorganic, Grade 3
    4
    3
        Phosphorus inorganic, Grade 4
    0
    0
        Total Bilirubin, Grade 3
    0
    2
        Total Bilirubin, Grade 4
    0
    1
        Alanine Amino Transferase ,Grade 3
    0
    1
        Alanine Amino Transferase ,Grade 4
    0
    0
        Calcium,Grade 3
    0
    0
        Calcium,Grade 4
    0
    0
        Chloride,Grade 3
    0
    0
        Chloride,Grade 4
    0
    0
        Cholesterol,Grade 3
    1
    1
        Cholesterol,Grade 4
    0
    0
        Creatine Kinase,Grade 3
    0
    0
        Creatine Kinase,Grade 4
    0
    0
        Direct Bilirubin,Grade 3
    0
    0
        Direct Bilirubin,Grade 4
    0
    0
        Glucose,Grade 3
    1
    0
        Glucose,Grade 4
    0
    1
        HDL Cholesterol direct,Grade 3
    0
    0
        HDL Cholesterol direct,Grade 4
    0
    0
        Lipase,Grade 3
    2
    3
        Lipase,Grade 4
    1
    1
        Potassium,Grade 3
    0
    0
        Potassium,Grade 4
    0
    0
        Sodium,Grade 3
    1
    0
        Sodium,Grade 4
    0
    0
        Total Cholesterol/HDLratio, Grade 3
    0
    0
        Total Cholesterol/HDLratio, Grade 4
    0
    0
        Triglycerides,Grade 3
    0
    2
        Triglycerides,Grade 4
    0
    0
        Urea/BUN,Grade 3
    0
    0
        Urea/BUN,Grade 4
    0
    0
    Notes
    [34] - Safety Population: all participants that took at least one dose of DTG
    [35] - Safety Population: all participants that took at least one dose of DTG
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated Grade 3 and Grade 4 hematological toxicities

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    End point title
    Number of participants with the indicated Grade 3 and Grade 4 hematological toxicities
    End point description
    Hematology and clinical chemistry data were summarized according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Potentially life-threatening. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. The Grade 3 and Grade 4 hematological toxicities included: Hemoglobin, Platelet Count, Total Neutrophils, and White Blood Cell count.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
    End point values
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Number of subjects analysed
    27 [36]
    24 [37]
    Units: Participants
        Hemoglobin, Grade 3
    0
    1
        Hemoglobin, Grade 4
    0
    0
        Platelet count, Grade 3
    0
    0
        Platelet count, Grade 4
    0
    0
        Total Neutrophils, Grade 3
    0
    0
        Total Neutrophils, Grade 4
    0
    2
        White Blood Cell count, Grade 3
    0
    0
        White Blood Cell, Grade 4
    0
    1
    Notes
    [36] - Safety Population: all participants that took at least one dose of DTG
    [37] - Safety Population: all participants that took at least one dose of DTG
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and non-serious AEs were collected from start of study treatment until the follow-up contact.
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in the Safety Population, comprised of all participants that took at least one dose of DTG.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cohort I (DTG 50 mg OD)
    Reporting group description
    Participants received dolutegravir (DTG) 50 milligrams (mg) once a day (OD).

    Reporting group title
    Cohort II (DTG 50 mg BID)
    Reporting group description
    Participants received DTG 50 mg twice a day (BID).

    Serious adverse events
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 27 (37.04%)
    11 / 24 (45.83%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Cryoglobulinaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunoblastic lymphoma
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (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
    Brain mass
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Dacryostenosis acquired
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anogenital dysplasia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic fibrosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Body fat disorder
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemochromatosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort I (DTG 50 mg OD) Cohort II (DTG 50 mg BID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 27 (92.59%)
    22 / 24 (91.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 27 (11.11%)
    7 / 24 (29.17%)
         occurrences all number
    4
    9
    Asthenia
         subjects affected / exposed
    6 / 27 (22.22%)
    3 / 24 (12.50%)
         occurrences all number
    6
    4
    Oedema peripheral
         subjects affected / exposed
    4 / 27 (14.81%)
    2 / 24 (8.33%)
         occurrences all number
    7
    2
    Fatigue
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    5
    Influenza like illness
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Injection site reaction
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    15
    Malaise
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 27 (18.52%)
    2 / 24 (8.33%)
         occurrences all number
    5
    2
    Anxiety
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Depressed mood
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    Depression
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Investigations
    Lipase increased
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    4
    Weight decreased
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 27 (18.52%)
    7 / 24 (29.17%)
         occurrences all number
    5
    10
    Dyspnoea
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Sinus congestion
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    7
    Oropharyngeal pain
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    3
    Nasal congestion
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 24 (16.67%)
         occurrences all number
    2
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 24 (12.50%)
         occurrences all number
    4
    3
    Sciatica
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Dizziness
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    Dysaesthesia
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 27 (29.63%)
    9 / 24 (37.50%)
         occurrences all number
    10
    15
    Abdominal pain upper
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 24 (12.50%)
         occurrences all number
    5
    4
    Constipation
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    4
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 27 (11.11%)
    2 / 24 (8.33%)
         occurrences all number
    3
    4
    Nausea
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 24 (12.50%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 24 (12.50%)
         occurrences all number
    6
    4
    Abdominal distension
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    2
    3
    Abdominal pain
         subjects affected / exposed
    4 / 27 (14.81%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Anogenital dysplasia
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Defaecation urgency
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Intertrigo
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 27 (18.52%)
    2 / 24 (8.33%)
         occurrences all number
    5
    2
    Back pain
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 24 (12.50%)
         occurrences all number
    3
    3
    Myalgia
         subjects affected / exposed
    4 / 27 (14.81%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Pain in extremity
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    8
    Osteoarthritis
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Muscle spasms
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Tendonitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Vitamin D deficiency
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 27 (22.22%)
    7 / 24 (29.17%)
         occurrences all number
    6
    12
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 24 (20.83%)
         occurrences all number
    2
    11
    Nasopharyngitis
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Gastroenteritis viral
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Influenza
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Oral herpes
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    4
    Ear infection
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Genital herpes
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Herpes virus infection
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Otitis media
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Rhinitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    Sinusitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    Tooth abscess
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jul 2009
    Amendment No 1.: Inclusion of final 9-month monkey toxicology data summary, update of the study design discussion sections based on the toxicology data, clarification of definition of evidence of resistance to antiretrovirals for eligibility, addition of an inclusion criterion, addition of resistance testing at Day 1 in the time and events table with a corresponding update of the Viral Genotyping and Phenotyping Section, update on requirements for PBMC collection in the time and events table, clarification of timing of pre-dose PK samples, correction of specification of etravirine use in one section of the protocol and correction of minor typographical errors.
    16 Sep 2009
    Amendment No 2.: Clarification of instructions for pregnancy testing at Day 1 to include urine pregnancy testing, addition of text on guidance and recommendations for timing of influenza vaccine, formatting correction of table in Section 6.3, other minor clarifications and correction of typographical errors.
    29 Apr 2010
    Amendment No. 3: This amendment details the inclusion of an additional cohort of subjects to receive DTG 50 mg twice daily (Cohort II), dose-rationale and PK-PD model to evaluate potential benefit of increasing the dose of DTG, and summarizes preliminary data from ING112961 Cohort I (50 mg), safety data from ING112276, preliminary data from ING111856 (QT Study). In addition, this amendment includes other minor clarifications and corrections of typographical errors.
    26 Aug 2010
    Amendment No.4: This amendment specifies a change of Study Sponsor, provides updated safety information from ING112961 Cohort I and ING112276 and specifies additional urinalyses. Removal of chronic NSAID use from prohibited medications.
    29 Aug 2011
    Amendment No.5: This amendment is to allow ongoing Cohort I subjects the option to receive DTG 50mg BID. Efficacy and safety information from Cohort II have been provided, the prohibited medication list and toxicity management updated.

    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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