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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Switching from a Regimen of Dolutegravir and Either Emtricitabine/Tenofovir Alafenamide or Emtricitabine/Tenofovir Disoproxil Fumarate to a Fixed Dose Combination of Bictegravir/ Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected Subjects who are Virologically Suppressed

    Summary
    EudraCT number
    		 2017-000308-17
    Trial protocol
    		 DE   AT   FR  
    Global end of trial date
    10 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-380-4030
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03110380
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    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
    10 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of switching from a regimen of either dolutegravir (DTG) and emtricitabine/tenofovir alafenamide (F/TAF) or DTG and emtricitabine/tenofovir disoproxil fumarate (F/TDF) to a fixed dose combination (FDC) of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus DTG+F/TAF in virologically suppressed HIV-1 infected adults with or without antiretroviral (ARV) resistance.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Puerto Rico: 32
    Country: Number of subjects enrolled
    United States: 401
    Worldwide total number of subjects
    567
    EEA total number of subjects
    85
    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)
    513
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America and Europe. The first participant was screened on 12 June 2017. The last study visit occurred on 10 Feb 2021.

    Pre-assignment
    Screening details
    		 633 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 B/F/TAF
    Arm description
    		 Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (50/200/25 mg) fixed-dose combination (FDC) tablet + dolutegravir (DTG) placebo tablet + emtricitabine/tenofovir alafenamide (F/TAF) placebo tablet administered orally once daily without regard to food for at least 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    B/F/TAF
    Investigational medicinal product code
    Other name
    GS-9883/F/TAF, Biktarvy, BVY
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg FDC administered orally once daily

    Investigational medicinal product name
    DTG Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg administered orally once daily

    Investigational medicinal product name
    F/TAF Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200/25 mg administered orally once daily

    Arm title
    		 DTG + F/TAF
    Arm description
    		 DTG 50 mg tablet + F/TAF (200/25 mg) FDC tablet + B/F/TAF placebo tablet administered orally once daily without regard to food for at least 48 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    F/TAF
    Investigational medicinal product code
    Other name
    Descovy®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200/25 mg FDC administered orally once daily

    Investigational medicinal product name
    B/F/TAF Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg administered orally once daily

    Investigational medicinal product name
    DTG
    Investigational medicinal product code
    Other name
    Tivicay®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg administered orally once daily

    Number of subjects in period 1 [1]
    		B/F/TAF DTG + F/TAF
    Started
    284
    281
    Completed
    263
    253
    Not completed
    21
    28
         Protocol violation
    -
    1
         Death
    2
    1
         Investigator's Discretion
    1
    3
         Non-compliance with study drug
    1
    1
         Adverse event
    3
    3
         Lost to follow-up
    4
    3
         Withdrew consent
    10
    16
    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: Two participants in DTG + F/TAF arm were randomized but was not treated.
    Period 2
    Period 2 title
    Open-label B/F/TAF Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 B/F/TAF From B/F/TAF
    Arm description
    		 Participants who received B/F/TAF in double-blind phase and from a country where B/F/TAF was not available were given the option to receive B/F/TAF orally once daily for up to 96 weeks in the open-label extension phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    B/F/TAF
    Investigational medicinal product code
    Other name
    GS-9883/F/TAF
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg FDC administered orally once daily

    Arm title
    		 B/F/TAF From DTG + F/TAF
    Arm description
    		 Participants who received DTG + F/TAF in double-blind phase and from a country where B/F/TAF was not available were given the option to receive B/F/TAF orally once daily for up to 96 weeks in the open-label extension phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    F/TAF
    Investigational medicinal product code
    Other name
    Descovy®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    fdc tablet 200/25 mg FDC tablet(s) administered orally once daily

    Investigational medicinal product name
    DTG
    Investigational medicinal product code
    Other name
    Tivicay®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg tablet 50 mg tablet(s) administered orally once daily

    Investigational medicinal product name
    B/F/TAF
    Investigational medicinal product code
    Other name
    GS-9883/F/TAF
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg administered orally once daily

    Number of subjects in period 2 [2]
    		B/F/TAF From B/F/TAF B/F/TAF From DTG + F/TAF
    Started
    125
    116
    Completed
    121
    113
    Not completed
    4
    3
         Adverse event
    -
    1
         Lost to follow-up
    3
    1
         Withdrew consent
    1
    1
    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: 138 participants in B/F/TAF arm completed the Double-Blind treatment phase, but did not enter in the Open-label B/F/TAF extension phase. 137 participants in DTG + F/TAF arm completed the Double-Blind treatment phase, but did not enter in the Open-label B/F/TAF extension phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    B/F/TAF
    Reporting group description
    		 Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (50/200/25 mg) fixed-dose combination (FDC) tablet + dolutegravir (DTG) placebo tablet + emtricitabine/tenofovir alafenamide (F/TAF) placebo tablet administered orally once daily without regard to food for at least 48 weeks.

    Reporting group title
    DTG + F/TAF
    Reporting group description
    		 DTG 50 mg tablet + F/TAF (200/25 mg) FDC tablet + B/F/TAF placebo tablet administered orally once daily without regard to food for at least 48 weeks.

    Reporting group values
    		 B/F/TAF DTG + F/TAF Total
    Number of subjects
    		 284 281 565
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50 ( 11.3 ) 49 ( 11.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 41 80
        Male
    		 245 240 485
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 3 3 6
        Black
    		 68 61 129
        Native Hawaiian or Pacific Islander
    		 2 1 3
        White
    		 200 199 399
        Other
    		 9 13 22
        Not Permitted
    		 2 3 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 61 49 110
        Not Hispanic or Latino
    		 220 229 449
        Not Permitted
    		 3 3 6

    End points

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    End points reporting groups
    Reporting group title
    B/F/TAF
    Reporting group description
    		 Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (50/200/25 mg) fixed-dose combination (FDC) tablet + dolutegravir (DTG) placebo tablet + emtricitabine/tenofovir alafenamide (F/TAF) placebo tablet administered orally once daily without regard to food for at least 48 weeks.

    Reporting group title
    DTG + F/TAF
    Reporting group description
    		 DTG 50 mg tablet + F/TAF (200/25 mg) FDC tablet + B/F/TAF placebo tablet administered orally once daily without regard to food for at least 48 weeks.
    Reporting group title
    B/F/TAF From B/F/TAF
    Reporting group description
    		 Participants who received B/F/TAF in double-blind phase and from a country where B/F/TAF was not available were given the option to receive B/F/TAF orally once daily for up to 96 weeks in the open-label extension phase.

    Reporting group title
    B/F/TAF From DTG + F/TAF
    Reporting group description
    		 Participants who received DTG + F/TAF in double-blind phase and from a country where B/F/TAF was not available were given the option to receive B/F/TAF orally once daily for up to 96 weeks in the open-label extension phase.

    Primary: Percentage of Participants with HIV-1 RNA ≥ 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm

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    End point title
    		 Percentage of Participants with HIV-1 RNA ≥ 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm
    End point description
    The percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. The Full Analysis Set included participants who were randomized and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 B/F/TAF DTG + F/TAF
    Number of subjects analysed
    284
    281
    Units: percentage of participants
        number (not applicable)
    0.4
    1.1
    Statistical analysis title
    		 B/F/TAF, DTG + F/TAF
    Statistical analysis description
    The null hypothesis was that the B/F/TAF group is at least 4% higher than the DTG + F/TAF group with respect to the percentage of participants with HIV-1 RNA ≥ 50 copies/mL as determined by the US FDA-defined snapshot algorithm at Week 48; the alternative hypothesis was that the B/F/TAF group is less than 4% higher than the DTG + F/TAF group with respect to the percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48.
    Comparison groups
    B/F/TAF v DTG + F/TAF
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 1
    Notes
    [1] - A sample size of 260 participants per treatment group would provide at least 90% power to detect a non-inferiority margin of 4% in difference in percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 between the two treatment groups. This was based on the assumptions that both treatment groups have 2% of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 (based on Gilead Genvoya and Stribild studies) and that the significance level of the test is at a one-sided 0.025 level.
    Statistical analysis title
    		 B/F/TAF, DTG + F/TAF
    Comparison groups
    B/F/TAF v DTG + F/TAF
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm

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    End point title
    		 Percentage of Participants with HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm
    End point description
    The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 B/F/TAF DTG + F/TAF
    Number of subjects analysed
    284
    281
    Units: percentage of participants
        number (not applicable)
    93.3
    91.1
    Statistical analysis title
    		 B/F/TAF, DTG + F/TAF
    Comparison groups
    DTG + F/TAF v B/F/TAF
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 6.8
    Notes
    [2] - It would be concluded that B/F/TAF is noninferior to DTG+F/TAF if the lower bound of the 2-sided 95.001% CI of the difference between treatment groups (B/F/TAF group –DTG+F/TAF group) in the percentage of participants with HIV-1 RNA < 50 copies/mL is greater than −10%.

    Secondary: Change From Baseline in CD4+ Cell Count at Week 48

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    End point title
    		 Change From Baseline in CD4+ Cell Count at Week 48
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 B/F/TAF DTG + F/TAF
    Number of subjects analysed
    262
    256
    Units: cells/μL
        arithmetic mean (standard deviation)
    18 ( 179.1 )
    36 ( 152.6 )
    Statistical analysis title
    		 B/F/TAF, DTG + F/TAF
    Comparison groups
    B/F/TAF v DTG + F/TAF
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23 [3]
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46
         upper limit
    		 11
    Notes
    [3] - P-value, difference in least squares means (LSM), and its 95% CI were from ANOVA model with treatment group as a fixed effect in the model.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events: First dose date up to last dose date [maximum: 84.9 weeks (Blinded Phase), 179.6 weeks (Open Label Phase) plus 30 days; All-Cause Mortality: Randomization/Enrollment up to 187.7 weeks
    Adverse event reporting additional description
    Adverse Events: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug. All-Cause Mortality: The All Randomized Analysis Set included all participants who were randomized into the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Double-Blind Treatment Phase B/F/TAF
    Reporting group description
    		 B/F/TAF (50/200/25 mg) FDC tablet + DTG placebo tablet + F/TAF placebo tablet administered orally once daily without regard to food for at least 48 weeks.

    Reporting group title
    Double-Blind Treatment Phase DTG + F/TAF
    Reporting group description
    		 DTG 50 mg tablet + F/TAF (200/25 mg) FDC tablet + B/F/TAF placebo tablet administered orally once daily without regard to food for at least 48 weeks.

    Reporting group title
    Open-label Extension Phase B/F/TAF from B/F/TAF
    Reporting group description
    		 Participants who received B/F/TAF in double-blind phase and from a country where B/F/TAF was not available were given the option to receive B/F/TAF orally once daily for up to 96 weeks in the open-label extension phase.

    Reporting group title
    Open-label Extension Phase B/F/TAF from DTG + F/TAF
    Reporting group description
    		 Participants who received DTG + F/TAF in double-blind phase and from a country where B/F/TAF was not available were given the option to receive B/F/TAF orally once daily for up to 96 weeks in the open-label extension phase.

    Serious adverse events
    		 Double-Blind Treatment Phase B/F/TAF Double-Blind Treatment Phase DTG + F/TAF Open-label Extension Phase B/F/TAF from B/F/TAF Open-label Extension Phase B/F/TAF from DTG + F/TAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 284 (12.68%)
    27 / 281 (9.61%)
    12 / 125 (9.60%)
    11 / 116 (9.48%)
         number of deaths (all causes)
    3
    2
    0
    0
         number of deaths resulting from adverse events
    1
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Yolk sac tumour site unspecified
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody ~ positive vasculitis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug abuse
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rebound psychosis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lisfranc fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    2 / 125 (1.60%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral artery dissection
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphocytic infiltration
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary dyskinesia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 281 (0.71%)
    0 / 125 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 281 (0.00%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 281 (0.36%)
    0 / 125 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    0 / 281 (0.00%)
    1 / 125 (0.80%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-Blind Treatment Phase B/F/TAF Double-Blind Treatment Phase DTG + F/TAF Open-label Extension Phase B/F/TAF from B/F/TAF Open-label Extension Phase B/F/TAF from DTG + F/TAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    181 / 284 (63.73%)
    170 / 281 (60.50%)
    30 / 125 (24.00%)
    33 / 116 (28.45%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 284 (5.28%)
    11 / 281 (3.91%)
    3 / 125 (2.40%)
    0 / 116 (0.00%)
         occurrences all number
    15
    11
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 284 (5.63%)
    23 / 281 (8.19%)
    1 / 125 (0.80%)
    4 / 116 (3.45%)
         occurrences all number
    17
    25
    1
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 284 (7.75%)
    9 / 281 (3.20%)
    1 / 125 (0.80%)
    7 / 116 (6.03%)
         occurrences all number
    22
    9
    1
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    26 / 284 (9.15%)
    35 / 281 (12.46%)
    4 / 125 (3.20%)
    7 / 116 (6.03%)
         occurrences all number
    26
    42
    4
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 284 (3.87%)
    16 / 281 (5.69%)
    4 / 125 (3.20%)
    2 / 116 (1.72%)
         occurrences all number
    11
    16
    4
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 284 (3.17%)
    15 / 281 (5.34%)
    0 / 125 (0.00%)
    2 / 116 (1.72%)
         occurrences all number
    12
    17
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    19 / 284 (6.69%)
    14 / 281 (4.98%)
    1 / 125 (0.80%)
    3 / 116 (2.59%)
         occurrences all number
    19
    14
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 284 (8.45%)
    21 / 281 (7.47%)
    4 / 125 (3.20%)
    4 / 116 (3.45%)
         occurrences all number
    25
    21
    4
    4
    Back pain
         subjects affected / exposed
    20 / 284 (7.04%)
    15 / 281 (5.34%)
    2 / 125 (1.60%)
    3 / 116 (2.59%)
         occurrences all number
    22
    16
    2
    3
    Pain in extremity
         subjects affected / exposed
    15 / 284 (5.28%)
    15 / 281 (5.34%)
    1 / 125 (0.80%)
    4 / 116 (3.45%)
         occurrences all number
    17
    15
    1
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 284 (11.62%)
    40 / 281 (14.23%)
    9 / 125 (7.20%)
    10 / 116 (8.62%)
         occurrences all number
    36
    46
    10
    14
    Nasopharyngitis
         subjects affected / exposed
    44 / 284 (15.49%)
    32 / 281 (11.39%)
    3 / 125 (2.40%)
    1 / 116 (0.86%)
         occurrences all number
    63
    46
    3
    2
    Bronchitis
         subjects affected / exposed
    18 / 284 (6.34%)
    14 / 281 (4.98%)
    4 / 125 (3.20%)
    5 / 116 (4.31%)
         occurrences all number
    21
    16
    4
    5
    Influenza
         subjects affected / exposed
    19 / 284 (6.69%)
    17 / 281 (6.05%)
    2 / 125 (1.60%)
    1 / 116 (0.86%)
         occurrences all number
    21
    19
    2
    1
    Sinusitis
         subjects affected / exposed
    16 / 284 (5.63%)
    11 / 281 (3.91%)
    1 / 125 (0.80%)
    4 / 116 (3.45%)
         occurrences all number
    17
    11
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2017
    Amendment 1: • Additional mutations were added to the list of nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutations, along with guidance on how to categorize participants who qualify for more than 1 resistance mutation category. • A review of eligibility by the Gilead medical monitor was added for participants who had documented genotypic or phenotypic resistance to multiple classes of antiretrovirals (ARVs) to ensure they had sufficient options available to construct a viable rescue regimen should they fail on study. • Participants with virologic failure who had poor adherence were tested for resistance development. • The independent data monitoring committee convened at an earlier time point to assess participant safety and efficacy.
    28 Jun 2018
    Amendment 2: • Information regarding the safety of dolutegravir (DTG) in early pregnancy was added to the protocol. • Additional guidance on unblinding in the event of a pregnancy during the study and guidance on the management of pregnancies that occurred in the study were added. • Pregnancy screening and contraceptive requirements for the study were updated. • Collection of the whole blood sample on Day 1 was clarified; a required whole blood sample was to be collected, and an optional whole blood sample for pharmacogenomics was to be collected if a separate pharmacogenomics consent was obtained.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32668455
    http://www.ncbi.nlm.nih.gov/pubmed/32701823
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