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    Clinical Trial Results:
    A Phase 3, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Switching from Regimens Consisting of Boosted Atazanavir or Darunavir plus either Emtricitabine/Tenofovir or Abacavir/Lamivudine to GS-9883/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed HIV-1 Infected Adults

    Summary
    EudraCT number
    		 2015-004011-20
    Trial protocol
    		 GB   DE   ES   BE   IT  
    Global end of trial date
    23 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2020
    First version publication date
    23 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-380-1878
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02603107
    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
    23 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2019
    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 to a fixed-dose combination (FDC) of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus continuing on a regimen consisting of boosted atazanavir (ATV) or darunavir (DRV) plus either emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) in HIV-1 infected adults who were virologically suppressed.
    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
    20 Nov 2015
    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
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Germany: 61
    Country: Number of subjects enrolled
    United States: 330
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    Dominican Republic: 11
    Country: Number of subjects enrolled
    Italy: 8
    Worldwide total number of subjects
    578
    EEA total number of subjects
    172
    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)
    556
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Dominican Republic, North America, Australia, and Europe. The first participant was screened on 20 November 2015. The last study visit occurred on 23 December 2019.

    Pre-assignment
    Screening details
    		 707 participants were screened.

    Period 1
    Period 1 title
    Randomisation Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    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 orally once daily for at least 48 weeks, without regard to food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bictegravir/emtricitabine/tenofovir alafenamide
    Investigational medicinal product code
    Other name
    Biktarvy®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg FDC administered once daily for 48 weeks

    Arm title
    		 Stay on Baseline Regimen (SBR)
    Arm description
    		 Participants remained on current antiretroviral (ARV) regimen consisting of ritonavir (RTV)-boosted or cobicistat (COBI)-boosted atazanavir (ATV) or darunavir (DRV), plus either emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (200/300 mg) FDC tablet or abacavir/lamivudine (ABC/3TC) (600/300 mg) FDC tablet administered orally once daily for at least 48 weeks with food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg coadministered orally with ATV or DRV once daily for 48 weeks

    Investigational medicinal product name
    Atazanavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered orally once daily for 48 weeks

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg administered orally once daily for 48 weeks

    Investigational medicinal product name
    Emtricitabine/tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Truvada®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200/300 mg FDC administered orally once daily for 48 weeks

    Investigational medicinal product name
    Abacavir/lamivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600/300 mg administered orally once daily for 48 weeks

    Number of subjects in period 1 [1]
    		B/F/TAF Stay on Baseline Regimen (SBR)
    Started
    290
    287
    Completed
    275
    266
    Not completed
    15
    21
         Protocol violation
    1
    -
         Death
    1
    1
         Adverse event
    2
    -
         Non-compliance with study drug
    1
    1
         Lost to follow-up
    1
    3
         Withdrew consent
    8
    15
         Investigator's discretion
    -
    1
         Lack of efficacy
    1
    -
    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: One participant randomised to the SBR group was never dosed with study drug due to a protocol violation.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Extension B/F/TAF from B/F/TAF
    Arm description
    		 After Week 48, participants in countries where B/F/TAF was not available were given the option to receive B/F/TAF for up to 96 additional weeks or until the product became accessible to participants through an access program, or until Gilead Sciences elected to discontinue the study in that country, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    B/F/TAF
    Investigational medicinal product code
    Other name
    Biktarvy®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg FDC administered once daily for 96 weeks.

    Arm title
    		 Extension B/F/TAF from SBR
    Arm description
    		 After Week 48, participants in countries where B/F/TAF was not available were given the option to receive B/F/TAF for up to 96 additional weeks or until the product became accessible to participants through an access program, or until Gilead Sciences elected to discontinue the study in that country, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    B/F/TAF
    Investigational medicinal product code
    Other name
    Biktarvy®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50/200/25 mg FDC administered once daily for 96 weeks.

    Number of subjects in period 2 [2]
    		Extension B/F/TAF from B/F/TAF Extension B/F/TAF from SBR
    Started
    272
    245
    Completed
    263
    232
    Not completed
    9
    13
         Protocol violation
    1
    -
         Pregnancy
    -
    3
         Adverse event
    -
    2
         Not treated in extension phase
    -
    1
         Lost to follow-up
    3
    3
         Withdrew consent
    3
    2
         Investigator's discretion
    2
    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: 3 participants randomised to B/F/TAF and 21 participants randomised to SBR did not enter the open-label extension B/F/TAF treatment 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 orally once daily for at least 48 weeks, without regard to food.

    Reporting group title
    Stay on Baseline Regimen (SBR)
    Reporting group description
    		 Participants remained on current antiretroviral (ARV) regimen consisting of ritonavir (RTV)-boosted or cobicistat (COBI)-boosted atazanavir (ATV) or darunavir (DRV), plus either emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (200/300 mg) FDC tablet or abacavir/lamivudine (ABC/3TC) (600/300 mg) FDC tablet administered orally once daily for at least 48 weeks with food.

    Reporting group values
    		 B/F/TAF Stay on Baseline Regimen (SBR) Total
    Number of subjects
    		 290 287 577
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47 ± 10.5 46 ± 10.5 -
    Gender categorical
    Units: Subjects
        Female
    		 47 53 100
        Male
    		 243 234 477
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 3 3 6
        Asian
    		 6 10 16
        Black
    		 79 72 151
        Native Hawaiian or Pacific Islander
    		 0 0 0
        White
    		 188 190 378
        Other
    		 14 12 26
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 60 47 107
        Not Hispanic or Latino
    		 230 240 470
    HIV-1 RNA Category
    Units: Subjects
        < 50 copies/mL
    		 285 277 562
        ≥ 50 copies/mL
    		 5 10 15
    CD4 Cell Count Category
    Units: Subjects
        < 50 cells/μL
    		 0 0 0
        ≥ 50 to < 200 cells/μL
    		 4 8 12
        ≥ 200 to < 350 cells/μL
    		 26 30 56
        ≥ 350 to < 500 cells/μL
    		 62 60 122
        ≥ 500 cells/μL
    		 198 189 387
    HIV Disease Status
    Units: Subjects
        Asymptomatic
    		 240 234 474
        Symptomatic HIV Infection
    		 16 20 36
        Acquired immunodeficiency syndrome
    		 34 33 67
    Prior ARV Regimen
    Units: Subjects
        Boosted ATV + ABC/3TC
    		 21 23 44
        Boosted DRV + ABC/3TC
    		 24 21 45
        Boosted ATV + FTC/TDF
    		 105 110 215
        Boosted DRV + FTC/TDF
    		 140 133 273
    CD4 Cell Count
    Units: cells/μL
        arithmetic mean (standard deviation)
    		 669 ± 303.4 657 ± 285.0 -

    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 orally once daily for at least 48 weeks, without regard to food.

    Reporting group title
    Stay on Baseline Regimen (SBR)
    Reporting group description
    		 Participants remained on current antiretroviral (ARV) regimen consisting of ritonavir (RTV)-boosted or cobicistat (COBI)-boosted atazanavir (ATV) or darunavir (DRV), plus either emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (200/300 mg) FDC tablet or abacavir/lamivudine (ABC/3TC) (600/300 mg) FDC tablet administered orally once daily for at least 48 weeks with food.
    Reporting group title
    Extension B/F/TAF from B/F/TAF
    Reporting group description
    		 After Week 48, participants in countries where B/F/TAF was not available were given the option to receive B/F/TAF for up to 96 additional weeks or until the product became accessible to participants through an access program, or until Gilead Sciences elected to discontinue the study in that country, whichever occurred first.

    Reporting group title
    Extension B/F/TAF from SBR
    Reporting group description
    		 After Week 48, participants in countries where B/F/TAF was not available were given the option to receive B/F/TAF for up to 96 additional weeks or until the product became accessible to participants through an access program, or until Gilead Sciences elected to discontinue the study in that country, whichever occurred first.

    Primary: Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 48 as Determined by the 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 Determined by the 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. Full Analysis Set included all participants who were randomised into the study and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 B/F/TAF Stay on Baseline Regimen (SBR)
    Number of subjects analysed
    290
    287
    Units: percentage of participants
        number (not applicable)
    1.7
    1.7
    Statistical analysis title
    		 B/F/TAF vs SBR
    Statistical analysis description
    The null hypothesis was that percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 in the B/F/TAF group was at least 4% higher than the rate in the SBR group; the alternative hypothesis was that the percentage of participants with HIV-1 RNA ≥ 50 copies/mL in the B/F/TAF group was less than 4% higher than that in the SBR group. The difference in percentages and its 95.002% confidence interval (CI) were calculated based on an unconditional exact method using 2 inverted 1-sided test.
    Comparison groups
    Stay on Baseline Regimen (SBR) v B/F/TAF
    Number of subjects included in analysis
    577
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 2.5
    Notes
    [1] - A sample size of 520 participants (260 participants per treatment group) would provide at least 90% power to establish a non-inferiority margin of 4% in the Week 48 response rate (HIV-1 RNA ≥ 50 copies/mL) between the 2 treatment groups. Sample size was based on the assumptions that both treatment groups have 2% of participants with HIV-1 RNA ≥ 50 copies/mL (based on Gilead Genvoya and Stribild studies) and that the significance level of the test is at a 1-sided 0.025 level.
    Statistical analysis title
    		 B/F/TAF vs SBR
    Comparison groups
    B/F/TAF v Stay on Baseline Regimen (SBR)
    Number of subjects included in analysis
    577
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Determined by the 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 Determined by the 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. Participants in the FAS were analysed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 B/F/TAF Stay on Baseline Regimen (SBR)
    Number of subjects analysed
    290
    287
    Units: percentage of participants
        number (not applicable)
    92.1
    88.9
    Statistical analysis title
    		 B/F/TAF vs SBR
    Comparison groups
    B/F/TAF v Stay on Baseline Regimen (SBR)
    Number of subjects included in analysis
    577
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 8.2
    Notes
    [2] - The non-inferiority of B/F/TAF would be established if the lower bound of the 2-sided 95.002% CI of the difference between the treatment groups (B/F/TAF group - SBR group) in the percentage of participants with HIV-1 RNA < 50 copies/mL is greater than -10%. The difference in percentages and its 95.002% confidence interval (CI) were calculated based on an unconditional exact method using 2 inverted 1-sided tests.
    Statistical analysis title
    		 B/F/TAF vs SBR
    Comparison groups
    B/F/TAF v Stay on Baseline Regimen (SBR)
    Number of subjects included in analysis
    577
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Change from Baseline in CD4 Cell Count

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    End point title
    		 Change from Baseline in CD4 Cell Count
    End point description
    Participants in the Full Analysis Set with available data were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 B/F/TAF Stay on Baseline Regimen (SBR)
    Number of subjects analysed
    265
    256
    Units: cells/μL
        arithmetic mean (standard deviation)
    25 ± 151.2
    0 ± 159.4
    Statistical analysis title
    		 B/F/TAF vs SBR
    Comparison groups
    B/F/TAF v Stay on Baseline Regimen (SBR)
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068
    Method
    		 ANOVA
    Parameter type
    		 Difference in Least Squares Means (LSM)
    Point estimate
    25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 52

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose date up to last dose date ( maximum: 181 weeks) plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set included participants who were randomized into the study and received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    B/F/TAF (Randomised Phase)
    Reporting group description
    		 B/F/TAF (50/200/25 mg) FDC tablet administered orally once daily for at least 48 weeks without regard to food.

    Reporting group title
    Stay on Baseline Regimen (SBR) (Randomised Phase)
    Reporting group description
    		 Participants remained on current ARV regimen consisting of RTV or COBI boosted ATV or DRV, plus either FTC/TDF (200/300 mg) FDC tablet or ABC/3TC (600/300 mg) FDC tablet administered orally once daily for at least 48 weeks with food.

    Reporting group title
    Extension B/F/TAF from B/F/TAF
    Reporting group description
    		 After Week 48, participants in countries where B/F/TAF was not available were given the option to receive B/F/TAF for up to 96 additional weeks or until the product became accessible to participants through an access program, or until Gilead Sciences elected to discontinue the study in that country, whichever occurred first. This arm included participants from the B/F/TAF (Randomised Phase).

    Reporting group title
    Extension B/F/TAF from SBR
    Reporting group description
    		 After Week 48, participants in countries where B/F/TAF was not available were given the option to receive B/F/TAF for up to 96 additional weeks or until the product became accessible to participants through an access program, or until Gilead Sciences elected to discontinue the study in that country, whichever occurred first. This arm included participants from the SBR (Randomised Phase).

    Serious adverse events
    		 B/F/TAF (Randomised Phase) Stay on Baseline Regimen (SBR) (Randomised Phase) Extension B/F/TAF from B/F/TAF Extension B/F/TAF from SBR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 290 (5.86%)
    21 / 287 (7.32%)
    20 / 272 (7.35%)
    29 / 244 (11.89%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Brain cancer metastatic
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Hypertensive crisis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Hypotension
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Hypovolaemic shock
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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 / 290 (0.34%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Social circumstances
    Physical assault
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Reproductive system and breast disorders
    Pelvic haematoma
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Priapism
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Asthma
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Dyspnoea
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Alcohol abuse
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Alcoholism
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Anxiety
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Mania
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Schizoaffective disorder
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Suicidal ideation
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    1 / 244 (0.41%)
         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
    Accident
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Acetabulum fracture
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Head injury
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Humerus fracture
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Joint dislocation
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Radius fracture
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Skin laceration
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 287 (0.35%)
    1 / 272 (0.37%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Coronary artery stenosis
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Bradycardia
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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 / 1
    Myxomatous mitral valve degeneration
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Sinus node dysfunction
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Cerebral infarction
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Cervical radiculopathy
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Thrombotic stroke
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Lymphadenitis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Eye disorders
    Optic disc disorder
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Anal fistula
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Diarrhoea
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Diverticular perforation
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Cholelithiasis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Ureteric stenosis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    1 / 272 (0.37%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    2 / 290 (0.69%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Pneumonia
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    1 / 244 (0.41%)
         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
    Cellulitis
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Erysipelas
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    1 / 244 (0.41%)
         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
    Localised infection
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    1 / 272 (0.37%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Acute hepatitis C
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Anal abscess
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Hepatitis C
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Infection
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Influenza
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Neurosyphilis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    1 / 272 (0.37%)
    0 / 244 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Stoma site abscess
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 287 (0.35%)
    0 / 272 (0.00%)
    0 / 244 (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
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    0 / 244 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 290 (0.00%)
    0 / 287 (0.00%)
    0 / 272 (0.00%)
    1 / 244 (0.41%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 B/F/TAF (Randomised Phase) Stay on Baseline Regimen (SBR) (Randomised Phase) Extension B/F/TAF from B/F/TAF Extension B/F/TAF from SBR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    117 / 290 (40.34%)
    126 / 287 (43.90%)
    108 / 272 (39.71%)
    113 / 244 (46.31%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 290 (11.72%)
    14 / 287 (4.88%)
    13 / 272 (4.78%)
    17 / 244 (6.97%)
         occurrences all number
    36
    18
    14
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    24 / 290 (8.28%)
    17 / 287 (5.92%)
    19 / 272 (6.99%)
    12 / 244 (4.92%)
         occurrences all number
    28
    18
    20
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 290 (4.14%)
    9 / 287 (3.14%)
    14 / 272 (5.15%)
    8 / 244 (3.28%)
         occurrences all number
    12
    10
    15
    10
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 290 (4.48%)
    19 / 287 (6.62%)
    15 / 272 (5.51%)
    13 / 244 (5.33%)
         occurrences all number
    16
    23
    15
    14
    Arthralgia
         subjects affected / exposed
    15 / 290 (5.17%)
    16 / 287 (5.57%)
    12 / 272 (4.41%)
    9 / 244 (3.69%)
         occurrences all number
    16
    16
    14
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    23 / 290 (7.93%)
    35 / 287 (12.20%)
    24 / 272 (8.82%)
    38 / 244 (15.57%)
         occurrences all number
    27
    48
    28
    54
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 290 (7.93%)
    24 / 287 (8.36%)
    24 / 272 (8.82%)
    27 / 244 (11.07%)
         occurrences all number
    25
    28
    27
    30
    Syphilis
         subjects affected / exposed
    9 / 290 (3.10%)
    11 / 287 (3.83%)
    14 / 272 (5.15%)
    14 / 244 (5.74%)
         occurrences all number
    9
    11
    16
    15
    Influenza
         subjects affected / exposed
    7 / 290 (2.41%)
    12 / 287 (4.18%)
    10 / 272 (3.68%)
    15 / 244 (6.15%)
         occurrences all number
    7
    18
    10
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2016
    Amendment 1: 1) Expanded the regions and number of sites participating in the study to include Latin America, 2) Included available data from the Week 24 primary endpoint of the Phase 2 Study GS-US-141-1475 in the introduction, 3) Added language to the Risk/Benefit Assessment for this Study section, 4) Updated inclusion criteria to remove the limit for the number of prior regimens at screening, 5) Clarified the criteria for discontinuation of study treatment and for management of laboratory toxicity, 6) Included guidance for the management of potential hepatobiliary toxicity.
    19 Oct 2016
    Amendment 2: 1) Increased the duration of the OL extension by an additional 48 weeks to allow subjects to continue receiving therapy without interruption in the event that B/F/TAF is not yet available via an access program, 2) Updated lists of BIC, BIC/F/TAF, and TAF clinical trials in the introduction, 3) Revised language in the Risk/Benefit Assessment for this Study section, 4) Revised the lists of prior and concomitant medications excluded or used with caution during the study, 5) Added PT/INR to the Day 1 assessments as it was previously missed in error, 6) Added hepatitis B virus (HBV) and hepatitis C virus (HCV) serology testing, 7) Added assessments to post-Week 48 visits to increase the frequency of assessments for continued safety monitoring due to the extension of the study duration, 8) Clarified assessments for the early study drugs discontinuation (ESDD) and 30-day follow-up visits, 9) Revised Gilead reporting requirements to clarify that, in addition to using the reference safety information in the investigator’s brochure and relevant local label as applicable, Gilead may also use the European Union summary of product characteristics (SmPC) (for the SBR treatment group medications) for the assessment of expectedness of serious adverse events (SAEs), 10) Revised the definition of special situations, 11) Allowed triggering of the independent data monitoring committee (IDMC) from the percentage of actual subjects enrolled for Week 12, which was based upon target sample size. The Week 12 IDMC was added to support the review of safety data in this virologically suppressed subject population.

    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/29925490
    http://www.ncbi.nlm.nih.gov/pubmed/31430369
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