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    Clinical Trial Results:
    A Phase 3, randomized, double-blind study of the safety and efficacy of GSK1349572 plus abacavir/lamivudine fixed-dose combination therapy administered once daily compared to Atripla over 96 weeks in HIV-1 infected antiretroviral therapy naive adult subjects.

    Summary
    EudraCT number
    		 2010-020983-39
    Trial protocol
    		 NL   DE   ES   GB   HU   DK   BE   IT  
    Global end of trial date
    03 Dec 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ING114467
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ViiV Healthcare
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    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
    24 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the antiviral activity of GSK1349572 plus ABC/3TC FDC once daily therapy compared to Atripla over 48 weeks in HIV-1 infected therapy-naive subjects.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 27 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Spain: 235
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 71
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Canada: 59
    Country: Number of subjects enrolled
    United States: 325
    Worldwide total number of subjects
    844
    EEA total number of subjects
    442
    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)
    837
    From 65 to 84 years
    6
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study consisted of 96 weeks double-blind phase, followed by a 48 week open-label phase.

    Pre-assignment
    Screening details
    		 A total of 844 participants (par.) were randomized (1:1) to one of the two treatment arms. Of these, 833 par. received at least one dose of study medication. Of the 11 par. who were randomized but not treated with investigational product, 7 par. withdrew consent, 3 par. were randomized in error, and 1 par. was lost to follow-up.

    Period 1
    Period 1 title
    Double-blind phase: 96 weeks duration
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Arm description
    		 During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks.
    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 tablet once daily for 96 weeks in double-blind randomized phase

    Investigational medicinal product name
    Abacavir/Lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600/300 mg tablet once daily for 96 weeks in double-blind randomized phase

    Investigational medicinal product name
    Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet once daily for 96 weeks in double-blind randomized phase.

    Arm title
    		 EFV/TDF/FTC 600/200/300 mg once daily
    Arm description
    		 During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600/200/300 mg tablet once daily for 96 weeks in double-blind randomized phase

    Investigational medicinal product name
    Dolutegravir (DTG) placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet once daily for 96 weeks in double-blind randomized phase

    Investigational medicinal product name
    Abacavir/Lamivudine (ABC/3TC) Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet once daily for 96 weeks in double-blind randomized phase

    Number of subjects in period 1 [1]
    		DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Started
    414
    419
    Completed
    342
    310
    Not completed
    72
    109
         Adverse event, serious fatal
    -
    2
         Physician decision
    1
    2
         Consent withdrawn by subject
    9
    15
         Adverse event, non-fatal
    13
    46
         Lost to follow-up
    17
    18
         Lack of efficacy
    18
    14
         Protocol deviation
    14
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 844 participants (par.) were randomized (1:1) to one of the two treatment arms. Of these, 833 par. received at least one dose of study medication. Of the 11 par. who were randomized but not treated with investigational product, 7 par. withdrew consent, 3 par. were randomized in error, and 1 par. was lost to follow-up.
    Period 2
    Period 2 title
    Open-label phase: 48 weeks duration
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Arm description
    		 Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dolutegravir (DTG)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg tablet once daily for 48 weeks in open-label phase (96 weeks through 144 week), and during open-label continuation phase until dolutegravir is commercially approved.

    Investigational medicinal product name
    Abacavir/Lamivudine (ABC/3TC)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600/300 mg tablet once daily for 48 weeks in open-label phase (96 weeks through 144 week), and during open-label continuation phase until dolutegravir is commercially approved.

    Arm title
    		 EFV/TDF/FTC 600/200/300 mg once daily
    Arm description
    		 Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600/200/300 mg tablet once daily for 48 weeks in open-label phase (96 weeks through 144 week).

    Number of subjects in period 2 [2]
    		DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Started
    341
    309
    Completed
    317
    278
    Not completed
    24
    31
         Consent withdrawn by subject
    3
    7
         Physician decision
    -
    2
         Adverse event, non-fatal
    3
    10
         Lost to follow-up
    8
    8
         Lack of efficacy
    7
    2
         Protocol deviation
    3
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One subject in each treatment group elected not to enter the Open-label phase; however, they are considered to have completed the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Reporting group description
    		 During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks.

    Reporting group title
    EFV/TDF/FTC 600/200/300 mg once daily
    Reporting group description
    		 During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks.

    Reporting group values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily Total
    Number of subjects
    		 414 419 833
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.5 ( 10.74 ) 36.4 ( 10.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 67 63 130
        Male
    		 347 356 703
    Race
    Units: Subjects
        African American (Af Am)/African Heritage (Af Ht)
    		 98 99 197
        American Indian (AI) or Alaska Native (Nat)
    		 13 17 30
        Asian
    		 9 9 18
        White
    		 284 285 569
        Af Am/Af Ht & AI or Alaska Native
    		 0 1 1
        Af Am/Af Ht & Nat Hawaiian/other Pacific Islander
    		 0 1 1
        Af Am/Af Ht & White
    		 3 2 5
        American Indian or Alaska Native & White
    		 6 4 10
        Asian & White
    		 1 0 1
        Missing
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Reporting group description
    		 During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks.

    Reporting group title
    EFV/TDF/FTC 600/200/300 mg once daily
    Reporting group description
    		 During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks.
    Reporting group title
    DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Reporting group description
    		 Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.

    Reporting group title
    EFV/TDF/FTC 600/200/300 mg once daily
    Reporting group description
    		 Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

    Subject analysis set title
    DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.

    Subject analysis set title
    EFV/TDF/FTC 600/200/300 mg once daily
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

    Primary: Proportion of Subjects Responding based on Plasma HIV-1 RNA <50 c/mL at Week 48

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    End point title
    		 Proportion of Subjects Responding based on Plasma HIV-1 RNA <50 c/mL at Week 48
    End point description
    The percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 48 was assessed. Plasma samples were collected for the quantitative assessment of HIV-1 RNA based on the Missing, Switch, or Discontinuation equals Failure (MSDF) algorithm, as codified by the Food and Drug Administration's Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to the visit window) as non-responders, as well as participants who switched their concomitant antiretroviral therapy (ART) in certain scenarios. Since changes in ART were not permitted in this protocol, all such participants who changed ART were to be considered non-responders. Otherwise, virologic success or failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the visit of interest window. Intent-to-Treat-Exposed (ITT-E) Population.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [1]
    419 [2]
    Units: Percentage of participants
        number (not applicable)
    88
    81
    Notes
    [1] - ITT-E Population: all randomized par. who received at least one dose of study medication
    [2] - ITT-E Population: all randomized par. who received at least one dose of study medication
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The estimated value reflects the percentage on DTG + ABC/3TC minus the percentage on EFV/TDF/FTC.
    Comparison groups
    DTG 50 mg plus ABC/3TC 600/300 mg once daily v EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.003 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in percentage
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 12.2
    Notes
    [3] - Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG + ABC/3TC minus EFV/TDF/FTC) in percentages between the two treatment arms was > -10%.
    [4] - P-value is for the test of superiority.

    Secondary: Time to viral suppression (<50 c/mL)

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    End point title
    		 Time to viral suppression (<50 c/mL)
    End point description
    Viral suppression is defined as the first viral load value<50 c/mL. The Kaplan-Meier method was used to estimate time to viral suppression, defined as the time from the first dose of study treatment until the first viral load value <50 c/mL was reached. Participants who withdrew for any reason without having suppressed prior to the analysis were censored.
    End point type
    Secondary
    End point timeframe
    From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC)
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [5]
    419 [6]
    Units: Days
        median (confidence interval 95%)
    28 (28 to 29)
    84 (83 to 84)
    Notes
    [5] - ITT-E Population
    [6] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with plasma human immunodeficiency virus -1 (HIV-1) ribonucleic acid (RNA) <50 copies/milliliter (c/mL) at Week 96 and Week 144

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    End point title
    		 Percentage of participants with plasma human immunodeficiency virus -1 (HIV-1) ribonucleic acid (RNA) <50 copies/milliliter (c/mL) at Week 96 and Week 144
    End point description
    The percentage of participants with plasma HIV-1 RNA <50 c/mL at Week 96 and Week 144 was assessed. Plasma samples were collected for the quantitative assessment of HIV-1 RNA based on the Missing, Switch, or Discontinuation equals Failure (MSDF) algorithm, as codified by the Food and Drug Administration's Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to the visit window) as non-responders, as well as participants who switched their concomitant antiretroviral therapy (ART) in certain scenarios. Since changes in ART were not permitted in this protocol, all such participants who changed ART were to be considered non-responders. Otherwise, virologic success or failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the visit of interest window.
    End point type
    Secondary
    End point timeframe
    Week 96 and Week 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [7]
    419 [8]
    Units: Percentage of participants
    number (not applicable)
        Week 96
    77
    70
        Week 144
    71
    63
    Notes
    [7] - ITT-E Population
    [8] - ITT-E Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 96:The estimated value reflects the percentage on DTG + ABC/3TC minus the percentage on EFV/TDF/FTC.
    Comparison groups
    DTG 50 mg plus ABC/3TC 600/300 mg once daily v EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 = 0.016 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in percentage
    Point estimate
    7.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 13.1
    Notes
    [9] - Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG + ABC/3TC minus EFV/TDF/FTC) in percentages between the two treatment arms was > -10%.
    [10] - P-value is for the test of superiority.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 144:Estimated value reflects the percentage on DTG + ABC/3TC minus the percentage on EFV/TDF/FTC.
    Comparison groups
    DTG 50 mg plus ABC/3TC 600/300 mg once daily v EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.01 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in percentage
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 14.6
    Notes
    [11] - Non-inferiority could be concluded if the lower bound of a two-sided 95% confidence interval for the difference (DTG + ABC/3TC minus EFV/TDF/FTC) in percentages between the two treatment arms was >-10%.
    [12] - P-value is for the test of superiority.

    Secondary: Number of participants with a confirmed plasma HIV-1 RNA level >=1000 c/mL at or after Week 16 and before Week 24, or a confirmed plasma HIV-1 RNA level >=200 c/mL at or after Week 24

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    End point title
    		 Number of participants with a confirmed plasma HIV-1 RNA level >=1000 c/mL at or after Week 16 and before Week 24, or a confirmed plasma HIV-1 RNA level >=200 c/mL at or after Week 24
    End point description
    Data are presented as Kaplan Meier estimates of virologic failure (VF), defined as a confirmed plasma HIV-1 RNA level >=1000 c/mL at or after Week 16 and before Week 24, or a confirmed plasma HIV-1 RNA level >=200 c/mL at or after Week 24. A plasma HIV-1 RNA value was considered to be confirmed failure if a consecutive measurement satisfied the same failure criterion. The number of participants who experienced autoimmune deficiency syndrome (AIDS) Clinical Trials Group (ACTG) VFs was measured. For participants who withdrew from the study/were not documented to have reached confirmed VF at the cut off date of the Week 48 analysis, time to VF was to be censored at the planned visit week of the last measured plasma HIV-1 RNA sample. Data for participants who missed three consecutive scheduled plasma HIV-1 RNA measurements were to be censored at the planned visit week of the last assessment prior to the 3 consecutive missed visits.
    End point type
    Secondary
    End point timeframe
    From Baseline until Week 144) (average of 877.4 days for DTG; average of 788.8 study days for EFV/TDF/FTC)
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [13]
    419 [14]
    Units: Participants
    number (not applicable)
        ACTG virologic failures
    11
    8
        Censored participants
    403
    411
    Notes
    [13] - ITT-E Population
    [14] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144

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    End point title
    		 Change from Baseline in plasma HIV-1 RNA at Weeks 2, 4, 8, 12, 16, 24, 32, 40,48, 60, 72, 84, 96, 108, 120, 132 and 144
    End point description
    Blood samples were collected for the measurement of HIV-1 RNA in plasma. Changes from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the indicated time points were assessed (represented by n=X, X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [15]
    419 [16]
    Units: log10 copies/mL
    arithmetic mean (standard deviation)
        Week 2, n=387, 376
    -2.46 ( 0.49 )
    -1.96 ( 0.46 )
        Week 4, n=404, 391
    -2.88 ( 0.58 )
    -2.25 ( 0.52 )
        Week 8, n=395, 386
    -2.99 ( 0.64 )
    -2.6 ( 0.6 )
        Week 12, n=394, 377
    -3.01 ( 0.7 )
    -2.85 ( 0.63 )
        Week 16, n=386, 366
    -3.03 ( 0.66 )
    -2.98 ( 0.65 )
        Week 24, n=389, 364
    -3.05 ( 0.69 )
    -3.01 ( 0.76 )
        Week 32, n=380, 355
    -3.04 ( 0.7 )
    -3.05 ( 0.72 )
        Week 40, n=370, 345
    -3.05 ( 0.68 )
    -3.04 ( 0.7 )
        Week 48, n=370, 343
    -3.03 ( 0.69 )
    -3.04 ( 0.69 )
        Week 60, n=360, 330
    -3.03 ( 0.67 )
    -3.05 ( 0.69 )
        Week 72, n=354, 320
    -3.03 ( 0.7 )
    -3.06 ( 0.7 )
        Week 84, n=353, 314
    -3.02 ( 0.7 )
    -3.07 ( 0.68 )
        Week 96, n=345, 310
    -2.99 ( 0.73 )
    -3.06 ( 0.68 )
        Week 108, n=340, 300
    -3.01 ( 0.71 )
    -3.08 ( 0.67 )
        Week 120, n=333, 289
    -3 ( 0.77 )
    -3.07 ( 0.67 )
        Week 132, n=323, 284
    -3.03 ( 0.68 )
    -3.06 ( 0.67 )
        Week 144, n=313,269
    -3.02 ( 0.72 )
    -3.04 ( 0.69 )
    Notes
    [15] - ITT-E Population
    [16] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ cell counts at Week 144

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    End point title
    		 Change from Baseline in CD4+ cell counts at Week 144
    End point description
    Cluster of differentiation (CD4) lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy. Change from Baseline was calculated as the Week 144 value minus the Baseline value. The least squares mean is the estimated mean change from Baseline in CD4+ cell counts at Week 144 calculated from a repeated measures model including the following covariates: treatment, visit, Baseline plasma HIV-1 RNA, Baseline CD4+ cell count, treatment*visit interaction, Baseline HIV-1 RNA*visit interaction, and Baseline CD4+ cell count*visit interaction. No assumptions were made about the correlations between a participant's readings of CD4+, i.e., the correlation matrix for within-participant errors is unstructured.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [17]
    419 [18]
    Units: cells per millimeters cubed (cells/mm^3)
        least squares mean (standard error)
    378.48 ( 10.99 )
    331.57 ( 11.59 )
    Notes
    [17] - ITT-E Population
    [18] - ITT-E Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    DTG 50 mg plus ABC/3TC 600/300 mg once daily v EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [19]
    P-value
    		 = 0.003 [20]
    Method
    		 Repeated Measure Mixed Model
    Confidence interval
    Notes
    [19] - Adjusted mean is the estimated mean change from baseline (BL) in CD4 + Cell Count at Week 144 in each arm calculated from a repeated measures model including the following covariates: treatment, visit, BL plasma HIV-1 RNA, BL CD4 cell count, treatment*visit interaction, BL HIV-1 RNA*visit interaction and BL CD4 cell count*visit interaction. No assumptions were made about the correlations between a par.’s readings of CD4 i.e. the correlation matrix for within-subject errors is unstructured.
    [20] - P-value is for the test of superiority.

    Secondary: Change from Baseline in CD4+ cell counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144

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    End point title
    		 Change from Baseline in CD4+ cell counts at Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144
    End point description
    CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy. Change from Baseline was calculated as the value at Indicated visit minus the Baseline value. Only those participants available at the indicated time points were assessed (represented by n=X, X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132 and 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [21]
    419 [22]
    Units: cells per millimeters cubed (cells/mm^3)
    arithmetic mean (standard deviation)
        Week 4, n=404,390
    117.6 ( 114.51 )
    80.9 ( 112.43 )
        Week 8, n=396,382
    164.6 ( 129.98 )
    124.4 ( 124.5 )
        Week 12, n=394,378
    187.5 ( 157.46 )
    153 ( 131.91 )
        Week 16, n=386,366
    214.7 ( 173.35 )
    174.1 ( 132.02 )
        Week 24, n=388,361
    216.9 ( 162.89 )
    177.8 ( 147.72 )
        Week 32, n=380,353
    250.5 ( 172.06 )
    208.1 ( 152.13 )
        Week 40, n=364,347
    265.5 ( 187.81 )
    216.2 ( 158.49 )
        Week 48, n=368,344
    267.5 ( 192.3 )
    209.5 ( 164.37 )
        Week 60, n=359,330
    271.3 ( 188.05 )
    235.3 ( 171.98 )
        Week 72, n=354,319
    306.1 ( 202.02 )
    269.6 ( 180.04 )
        Week 84, n=352,314
    315.2 ( 197.92 )
    272.1 ( 172.28 )
        Week 96, n=343,309
    322.6 ( 205.35 )
    286 ( 195.7 )
        Week 108, n=339,300
    349.3 ( 218.76 )
    298.9 ( 188.41 )
        Week 120, n=332,287
    347 ( 234.96 )
    311 ( 198.79 )
        Week 132, n=323,283
    377.9 ( 205.78 )
    327.2 ( 175.31 )
        Week 144, n=313,270
    379.5 ( 221.17 )
    333.3 ( 189.25 )
    Notes
    [21] - ITT-E Population
    [22] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated post-baseline HIV-associated conditions and progression, excluding recurrences at Week 144

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    End point title
    		 Number of participants with the indicated post-baseline HIV-associated conditions and progression, excluding recurrences at Week 144
    End point description
    Clinical disease progression (CDP) was assessed according to the Centers for Disease Control and Prevention (CDC) HIV-1 classification system. Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition. Indicators of CDP were defined as: CDC CAT A at Baseline (BS) to a CDC CAT C event (EV); CDC CAT B at BS to a CDC CAT C EV; CDC CAT C at BS to a new CDC CAT C EV; or CDC CAT A, B, or C at BS to death.
    End point type
    Secondary
    End point timeframe
    From Baseline until Week 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [23]
    419 [24]
    Units: Participants
    number (not applicable)
        Week 144, Any category condition
    17
    24
        Week 144, Any Category B condition
    12
    17
        Week 144, Any Category C condition
    5
    6
        Week 144, Any death
    0
    2
        Week 144, Progression from CAT A to CAT C
    4
    4
        Week 144, Progression from CAT C to new CAT C
    1
    2
        Week 144, Progression from CAT A, B, or C to death
    0
    2
    Notes
    [23] - ITT-E Population
    [24] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated Grade 1 to 4 clinical and hematology toxicities at Week 144

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    End point title
    		 Number of participants with the indicated Grade 1 to 4 clinical and hematology toxicities at Week 144
    End point description
    All Grade 1 to 4 post-Baseline-emergent chemistry toxicities included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), asparate aminotransferase (AST), carbon dioxide (CO2) content/bicarbonate, cholesterol, creatine kinase (CK), creatinine, hyperglycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, low density lipoprotein (LDL) cholesterol calculation, lipase, phosphorus inorganic, total bilirubin, and triglycerides. All Grade 1 to 4 post-Baseline-emergent hematology toxicities included hemoglobin, platelet count, total neutrophils, and white blood cell count. The Division of AIDS (DAIDS) defined toxicity grades as follows: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening; Grade 5, death.
    End point type
    Secondary
    End point timeframe
    From Baseline until Week 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    414 [25]
    419 [26]
    Units: Participants
    number (not applicable)
        Week 144, ALT
    62
    81
        Week 144, Albumin
    0
    1
        Week 144, ALP
    17
    53
        Week 144, AST
    77
    85
        Week 144, CO2 content/bicarbonate
    135
    134
        Week 144, Cholesterol
    156
    140
        Week 144, CK
    91
    79
        Week 144, Creatinine
    17
    6
        Week 144, Hyperglycaemia
    121
    105
        Week 144, Hyperkalemia
    4
    12
        Week 144, Hypernatremia
    11
    9
        Week 144, Hypoglycaemia
    24
    21
        Week 144, Hypokalemia
    38
    21
        Week 144, Hyponatremia
    63
    86
        Week 144, LDL cholesterol calculation
    124
    111
        Week 144, Lipase
    111
    110
        Week 144, Phosphorus, inorganic
    109
    134
        Week 144, Total bilirubin
    22
    4
        Week 144, Triglycerides
    11
    11
        Week 144, Hemoglobin
    7
    11
        Week 144, Platelet count
    20
    19
        Week 144, Total neutrophils
    70
    80
        Week 144, White Blood Cell count
    9
    18
    Notes
    [25] - Safety Population: all participants who received at least one dose of investigational product
    [26] - Safety Population: all participants who received at least one dose of investigational product
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated genotypic resistance with virological failure (VF) through Week 144

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    End point title
    		 Number of participants with the indicated genotypic resistance with virological failure (VF) through Week 144
    End point description
    Whole blood samples were collected from participants to provide plasma for storage samples for potential viral genotypic and phenotypic analyses. Participants with confirmed virological failure (confirmed HIV-1 RNA >=50 copies/mL throughout the study and/or confirmed HIV-1 RNA >=200 copies/mL at Week 144) had plasma samples tested for HIV-1 RT genotype and HIV-1 integrase genotype from Baseline samples and from samples collected at the time of virological failure. Genotype testing was conducted at Day 1 and at the time of suspected protocol-defined virological failure (PDVF). A genotyping assessment was made of change across all amino acids within the integrase (IN)-encoding region, with particular attention paid to specific amino acid changes associated with the development of resistance to RAL, ELV, or DTG. PDVF Genotypic Population: all participants in the ITT-E Population with available on-treatment genotypic resistance data at the time of PDVF.
    End point type
    Secondary
    End point timeframe
    Through Week 144
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    26 [27]
    16 [28]
    Units: Participants
    number (not applicable)
        Week 144, RT mutation K65K/R
    0
    1
        Week 144, RT mutation K101E
    0
    1
        Week 144, RT mutation K103K/N
    0
    2
        Week 144, RT mutation K103N
    0
    2
        Week 144, RT mutation G190G/A
    0
    2
    Notes
    [27] - PDVF Genotypic Population
    [28] - PDVF Genotypic Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Symptom Bother Score (SBS) at Week 4 through Week 48

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    End point title
    		 Change from Baseline in the Symptom Bother Score (SBS) at Week 4 through Week 48
    End point description
    The Symptom Distress Module (SDM) is a 20-item, self-reported questionnaire measuring the presence/perceived distress linked to symptoms associated with HIV/its treatments. Developed with support from the AIDS Clinical Trials Group of the U.S. National Institute of Allergy and Infectious Diseases, it has demonstrated construct validity and has shown strong associations with physical/mental health summary scores and with disease severity. The SDM consists of 2 main scores: symptom count and the SBS, ranging from 0 (best) to 80 (worst) and based on the degree of bother that each symptom present posed. The SBS was calculated by adding the 20 individual bother item scores, which were calculated as: 0, “I do not have this symptom”; 1, "It doesn’t bother me”; 2, “It bothers me a little”; 3, “It bothers me”; 4, "It bothers me a lot." Estimates are calculated from an analysis of covariance (ANCOVA) model adjusting for age, sex, race, Baseline (BL) viral load, BL CD4+ cell count, and BL SBS.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 through 48 Par. with missing bother item scores at Week 4 had their last observation carried forward (LOCF). Only those par. contributing to the model (i.e., without missing response variables after LOCF or covariates) were analyzed.
    End point values
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Number of subjects analysed
    394 [29]
    393 [30]
    Units: Scores on a scale
        least squares mean (standard error)
    -1.818 ( 0.3849 )
    -1.246 ( 0.3854 )
    Notes
    [29] - ITT-E Population
    [30] - ITT-E Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to Week 144 (average of 877.4 study days for DTG; average of 788.8 study days for EFV/TDF/FTC).
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants who received at least one dose of investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    DTG 50 mg plus ABC/3TC 600/300 mg once daily
    Reporting group description
    		 During double-blind phase, participants received a dolutegravir (DTG) 50 milligram (mg) tablet along with an Abacavir/Lamivudine (ABC/3TC) 600/300 mg tablet once daily (OD) orally, with placebo to match Efavirenz/Tenofovir disoproxil fumarate/Emtricitabine (EFV/TDF/FTC) 600/200/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive DTG 50 mg tablet along with ABC/3TC 600/300 mg tablet OD orally, for additional 48 weeks during open-label phase.

    Reporting group title
    EFV/TDF/FTC 600/200/300 mg once daily
    Reporting group description
    		 During double-blind phase, participants received EFV/TDF/FTC 600/200/300 mg OD, with placebo to match DTG 50 mg and ABC/3TC 600/300 mg for 96 weeks. Participants who completed double-blind phase continued to receive EFV/TDF/FTC 600/200/300 mg OD for additional 48 weeks during open-label phase.

    Serious adverse events
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 414 (15.70%)
    60 / 419 (14.32%)
         number of deaths (all causes)
    0
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancoast's tumour
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleomorphic adenoma
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 414 (0.24%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Priapism
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar disorder
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    3 / 414 (0.72%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 414 (0.24%)
    3 / 419 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 414 (0.48%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervousness
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality disorder
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shared psychotic disorder
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical burn of skin
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (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
    Syncope
         subjects affected / exposed
    0 / 414 (0.00%)
    3 / 419 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal failure chronic
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    4 / 414 (0.97%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 414 (0.24%)
    3 / 419 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 414 (0.48%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 414 (0.24%)
    2 / 419 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 414 (0.00%)
    3 / 419 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syphilis
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AIDS dementia complex
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis pharyngeal
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium avium complex infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         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 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxoplasmosis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 419 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (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
    Diabetes mellitus
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 419 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DTG 50 mg plus ABC/3TC 600/300 mg once daily EFV/TDF/FTC 600/200/300 mg once daily
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    332 / 414 (80.19%)
    358 / 419 (85.44%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    23 / 414 (5.56%)
    17 / 419 (4.06%)
         occurrences all number
    25
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    43 / 414 (10.39%)
    154 / 419 (36.75%)
         occurrences all number
    49
    177
    Headache
         subjects affected / exposed
    67 / 414 (16.18%)
    64 / 419 (15.27%)
         occurrences all number
    82
    81
    Somnolence
         subjects affected / exposed
    10 / 414 (2.42%)
    24 / 419 (5.73%)
         occurrences all number
    12
    25
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    67 / 414 (16.18%)
    56 / 419 (13.37%)
         occurrences all number
    77
    64
    Pyrexia
         subjects affected / exposed
    27 / 414 (6.52%)
    30 / 419 (7.16%)
         occurrences all number
    32
    31
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    94 / 414 (22.71%)
    89 / 419 (21.24%)
         occurrences all number
    125
    109
    Nausea
         subjects affected / exposed
    70 / 414 (16.91%)
    63 / 419 (15.04%)
         occurrences all number
    82
    68
    Vomiting
         subjects affected / exposed
    28 / 414 (6.76%)
    27 / 419 (6.44%)
         occurrences all number
    34
    36
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 414 (9.42%)
    40 / 419 (9.55%)
         occurrences all number
    43
    44
    Oropharyngeal pain
         subjects affected / exposed
    32 / 414 (7.73%)
    19 / 419 (4.53%)
         occurrences all number
    39
    21
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    22 / 414 (5.31%)
    63 / 419 (15.04%)
         occurrences all number
    24
    71
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    74 / 414 (17.87%)
    52 / 419 (12.41%)
         occurrences all number
    89
    57
    Abnormal dreams
         subjects affected / exposed
    32 / 414 (7.73%)
    74 / 419 (17.66%)
         occurrences all number
    34
    81
    Depression
         subjects affected / exposed
    34 / 414 (8.21%)
    38 / 419 (9.07%)
         occurrences all number
    39
    40
    Anxiety
         subjects affected / exposed
    33 / 414 (7.97%)
    35 / 419 (8.35%)
         occurrences all number
    38
    42
    Nightmare
         subjects affected / exposed
    11 / 414 (2.66%)
    21 / 419 (5.01%)
         occurrences all number
    12
    26
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    37 / 414 (8.94%)
    25 / 419 (5.97%)
         occurrences all number
    44
    27
    Arthralgia
         subjects affected / exposed
    28 / 414 (6.76%)
    24 / 419 (5.73%)
         occurrences all number
    36
    31
    Pain in extremity
         subjects affected / exposed
    23 / 414 (5.56%)
    14 / 419 (3.34%)
         occurrences all number
    25
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    86 / 414 (20.77%)
    81 / 419 (19.33%)
         occurrences all number
    137
    124
    Upper respiratory tract infection
         subjects affected / exposed
    69 / 414 (16.67%)
    58 / 419 (13.84%)
         occurrences all number
    95
    84
    Bronchitis
         subjects affected / exposed
    33 / 414 (7.97%)
    33 / 419 (7.88%)
         occurrences all number
    39
    37
    Syphilis
         subjects affected / exposed
    26 / 414 (6.28%)
    31 / 419 (7.40%)
         occurrences all number
    28
    33
    Sinusitis
         subjects affected / exposed
    29 / 414 (7.00%)
    18 / 419 (4.30%)
         occurrences all number
    35
    21
    Influenza
         subjects affected / exposed
    31 / 414 (7.49%)
    14 / 419 (3.34%)
         occurrences all number
    35
    15
    Gastroenteritis
         subjects affected / exposed
    26 / 414 (6.28%)
    18 / 419 (4.30%)
         occurrences all number
    28
    22

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2010
    Country Specific Amendment for the United Kingdom
    14 Jan 2011
    This amendment includes the addition of standard hematology and clinical chemistry laboratory assessments as being required for all subjects at the Week 2 study visit. Minor clarifications and corrections have been incorporated.
    10 Oct 2011
    This amendment allows for a change in the management of subjects with protocol-defined virologic failure. Additional follow-up assessments were added to the Liver Chemistry Stopping criteria panel. Planned exploratory bone biomarkers results will not be reported to investigators with one exception.
    01 Aug 2012
    This amendment adds an Open-label Randomized Phase to both treatment arms from Week 96 to Week 144 to collect long term efficacy and safety data.
    17 Aug 2012
    This amendment enables the use of both the commercial presentation of Atripla and the overcoated Atripla in the Open-label Randomized Phase from Week 96 to Week 144.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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