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    Clinical Trial Results:
    A Multi-arm, Phase 3, Randomized, Placebo Controlled, Double Blind Clinical Trial to Investigate the Efficacy and Safety of Fostemsavir (BMS-663068/GSK3684934) in Heavily Treatment Experienced Subjects Infected with Multi-drug Resistant HIV-1 (BRIGHTE Study)

    Summary
    EudraCT number
    2014-002111-41
    Trial protocol
    ES   DE   BE   NL   GB   NO   IE   PT   GR   FR   RO  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Aug 2018
    First version publication date
    18 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    205888
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Other Identifier: Bristol-Myers Squibb: AI438-047
    Sponsors
    Sponsor organisation name
    ViiV Healthcare
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    14 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this Phase 3 study is to demonstrate that fostemsavir 600 mg BID has superior efficacy compared to placebo when given in combination with a failing background regimen over a period of 7 days in HIV-1 infected HTE adults with multi-drug resistance.
    Protection of trial subjects
    Not applicable
    Background therapy
    Participants continued to receive their current failing antiretroviral regimen along with fostemsavir 600 mg BID or placebo during the double-blind period. During open-label period, participants received an optimized background therapy along with fostemsavir 600 mg BID.
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 136
    Country: Number of subjects enrolled
    Argentina: 38
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 64
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Chile: 11
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Puerto Rico: 5
    Country: Number of subjects enrolled
    Romania: 9
    Worldwide total number of subjects
    371
    EEA total number of subjects
    79
    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)
    1
    Adults (18-64 years)
    358
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a 2 cohort Phase 3 study conducted in heavily treatment experienced (HTE) participants infected with multi-drug resistant human immunodeficiency virus (HIV)-1. Based on the number of fully active and available antiretroviral drug classes at Screening, participants were assigned to either Randomized Cohort or Non-randomized Cohort.

    Pre-assignment
    Screening details
    A total of 731 participants were screened, of which 371 were included in either Randomized Cohort (fostemsavir or placebo) or Non-randomized Cohort (fostemsavir) and received at least one dose of study treatment. The study was conducted in 24 countries. The results presented are based on the Week 48 Interim Analysis.

    Period 1
    Period 1 title
    Double-blind Period-Up to 8 days
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Randomized Cohort-Placebo
    Arm description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received placebo twice daily (BID) along with their currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID with an optimized background therapy (OBT).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one tablet of fostemsavir matched placebo twice daily with or without food.

    Arm title
    Randomized Cohort-fostemsavir 600 mg BID
    Arm description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received fostemsavir 600 milligram (mg) BID along with currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants continued to receive fostemsavir 600 mg BID with an OBT.
    Arm type
    Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 600 milligram (mg) tablet of fostemsavir twice daily with or without food.

    Arm title
    Non-randomized Cohort-fostemsavir 600 mg BID
    Arm description
    HTE HIV-1 infected participants with no remaining classes of fully active antiretroviral that could be combined in a new drug regimen were included in the Non-randomized Cohort. Participants received fostemsavir 600 mg BID in combination with OBT.
    Arm type
    Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 600 milligram (mg) tablet of fostemsavir twice daily with or without food.

    Number of subjects in period 1
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID Non-randomized Cohort-fostemsavir 600 mg BID
    Started
    69
    203
    99
    Completed
    68
    198
    99
    Not completed
    1
    5
    0
         No longer meets study criteria
    -
    1
    -
         Death
    1
    1
    -
         Adverse event, non-fatal
    -
    2
    -
         Lost to follow-up
    -
    1
    -
    Period 2
    Period 2 title
    Open label Period-Up to atleast 96 weeks
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Randomized Cohort-Placebo
    Arm description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received placebo twice daily (BID) along with their currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID with an optimized background therapy (OBT).
    Arm type
    Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 600 milligram (mg) tablet of fostemsavir twice daily with or without food.

    Arm title
    Randomized Cohort-fostemsavir 600 mg BID
    Arm description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received fostemsavir 600 milligram (mg) BID along with currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants continued to receive fostemsavir 600 mg BID with an OBT.
    Arm type
    Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 600 milligram (mg) tablet of fostemsavir twice daily with or without food.

    Arm title
    Non-randomized Cohort-fostemsavir 600 mg BID
    Arm description
    HTE HIV-1 infected participants with no remaining classes of fully active antiretroviral that could be combined in a new drug regimen were included in the Non-randomized Cohort. Participants received fostemsavir 600 mg BID in combination with OBT.
    Arm type
    Experimental

    Investigational medicinal product name
    Fostemsavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered one 600 milligram (mg) tablet of fostemsavir twice daily with or without food.

    Number of subjects in period 2
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID Non-randomized Cohort-fostemsavir 600 mg BID
    Started
    68
    198
    99
    Completed
    0
    0
    0
    Not completed
    68
    198
    99
         No longer meets study criteria
    -
    2
    2
         Death
    1
    5
    12
         Non-compliance with study drug
    3
    8
    5
         Lack of efficacy
    3
    9
    6
         Pregnancy
    -
    1
    -
         Progression of disease
    -
    1
    -
         Adverse event, serious fatal
    1
    2
    1
         Adverse event, non-fatal
    2
    2
    4
         Consent withdrawn by subject
    -
    5
    1
         Ongoing
    55
    160
    67
         Lost to follow-up
    3
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomized Cohort-Placebo
    Reporting group description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received placebo twice daily (BID) along with their currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID with an optimized background therapy (OBT).

    Reporting group title
    Randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received fostemsavir 600 milligram (mg) BID along with currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants continued to receive fostemsavir 600 mg BID with an OBT.

    Reporting group title
    Non-randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    HTE HIV-1 infected participants with no remaining classes of fully active antiretroviral that could be combined in a new drug regimen were included in the Non-randomized Cohort. Participants received fostemsavir 600 mg BID in combination with OBT.

    Reporting group values
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID Non-randomized Cohort-fostemsavir 600 mg BID Total
    Number of subjects
    69 203 99
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.0 ± 11.02 45.2 ± 12.72 48.1 ± 11.53 -
    Gender categorical
    Units: Subjects
        Female
    12 60 10 82
        Male
    57 143 89 289
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    18 42 23 83
        American Indian or Alaska Native
    1 6 1 8
        Asian
    0 2 0 2
        Native Hawaiian or other Pacific islander
    0 1 0 1
        White
    47 137 73 257
        Mixed
    1 6 1 8
        Hispanic
    1 2 1 4
        Mestizo
    1 2 0 3
        North African
    0 1 0 1
        Mulatto
    0 1 0 1
        Brown
    0 2 0 2
        White and African descent
    0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Randomized Cohort-Placebo
    Reporting group description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received placebo twice daily (BID) along with their currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID with an optimized background therapy (OBT).

    Reporting group title
    Randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received fostemsavir 600 milligram (mg) BID along with currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants continued to receive fostemsavir 600 mg BID with an OBT.

    Reporting group title
    Non-randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    HTE HIV-1 infected participants with no remaining classes of fully active antiretroviral that could be combined in a new drug regimen were included in the Non-randomized Cohort. Participants received fostemsavir 600 mg BID in combination with OBT.
    Reporting group title
    Randomized Cohort-Placebo
    Reporting group description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received placebo twice daily (BID) along with their currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID with an optimized background therapy (OBT).

    Reporting group title
    Randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants received fostemsavir 600 milligram (mg) BID along with currently failing antiretroviral regimen for 8 days during the randomized, double-blind period. During the open-label period, all participants continued to receive fostemsavir 600 mg BID with an OBT.

    Reporting group title
    Non-randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    HTE HIV-1 infected participants with no remaining classes of fully active antiretroviral that could be combined in a new drug regimen were included in the Non-randomized Cohort. Participants received fostemsavir 600 mg BID in combination with OBT.

    Subject analysis set title
    Randomized cohort
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    HTE HIV-1 infected participants with <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen were included in the Randomized Cohort. Participants were randomized to receive fostemsavir 600 mg BID or placebo along with their current failing antiretroviral regimen during the double-blind period for 8 days. During the open-label period, all participants received open-label fostemsavir 600 mg BID in combination with OBT for at least 96 weeks

    Primary: Mean change in logarithm to the base 10 (log10) HIV-1 ribonucleic acid (RNA) from Day 1 at Day 8-Randomized Cohort

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    End point title
    Mean change in logarithm to the base 10 (log10) HIV-1 ribonucleic acid (RNA) from Day 1 at Day 8-Randomized Cohort [1]
    End point description
    Plasma samples were collected for analysis of HIV-1 RNA. Mean change in log10 HIV-1 RNA from Day 1 was estimated using analysis of covariance (ANCOVA) with log10 HIV-1 RNA change from Day 1 at Day 8 as dependent variable, treatment (fostemsavir or placebo) as an independent variable, and Day 1 log10 HIV-1 RNA as a continuous covariate. Change from Day 1 was calculated as value at Day 8 minus value at Day 1. The analysis was performed on Intent-to-Treat Exposed (ITT-E) Population which comprised of all randomized participants who received at least one dose of study treatment. Missing HIV-1 RNA values at Day 8 were imputed using (a) Day 1 Observation Carried Forward (D1OCF) for participants without a value during blinded treatment (i.e, imputing a zero change from Day 1) or (b) Last Observation Carried Forward (LOCF) for participants with an early value during blinded treatment before the Day 8 analysis visit window. Participants with missing Day 1 HIV-1 RNA values were not analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 and Day 8
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is evaluated only in the Randomized cohort as pre-specified in the protocol and reporting and analysis plan.
    End point values
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects analysed
    69 [2]
    201 [3]
    Units: Log10 copies per milliliter (c/mL)
    least squares mean (confidence interval 95%)
        Log10 copies per milliliter (c/mL)
    -0.166 (-0.326 to -0.007)
    -0.791 (-0.885 to -0.698)
    Notes
    [2] - ITT-E Population
    [3] - ITT-E Population
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Difference in covariate-adjusted least squares means between treatment groups (Fostemsavir 600 mg BID-Placebo) is presented.
    Comparison groups
    Randomized Cohort-fostemsavir 600 mg BID v Randomized Cohort-Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.625
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    -0.441
    Notes
    [4] - Hypothesis test:µfostemsavir=µPlacebo where µ is a common intercept.

    Secondary: Percentage of participants with HIV-1 RNA decreases from Day 1 that exceed 0.5 log10 c/mL and 1.0 log10 c/mL at Day 8-Randomized cohort

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    End point title
    Percentage of participants with HIV-1 RNA decreases from Day 1 that exceed 0.5 log10 c/mL and 1.0 log10 c/mL at Day 8-Randomized cohort [5]
    End point description
    The percentage of participants in the Randomized Cohort with HIV-1 RNA decreases from Day 1 that exceed 0.5 log10 c/mL and 1.0 log10 c/mL at Day 8 was determined by comparing HIV-1 RNA Day 1 measurement of each participant to their Day 8 measurement. This was an ITT analysis that classified participants without HIV-1 RNA at Day 1 or Day 8 as failures. The percentage of responders along with 95% confidence interval based on Wilson score is presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 8
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is evaluated only in the Randomized cohort as pre-specified in the protocol and reporting and analysis plan.
    End point values
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects analysed
    69 [6]
    203 [7]
    Units: Percentage of participants
    number (confidence interval 95%)
        >0.5 log10 c/mL
    18.84 (11.35 to 29.61)
    64.53 (57.74 to 70.79)
        >1.0 log10 c/mL
    10.14 (5.00 to 19.49)
    45.81 (39.10 to 52.68)
    Notes
    [6] - ITT-E Population
    [7] - ITT-E Population
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Difference between treatment groups (fostemsavir 600 mg BID-Placebo) and 95% confidence interval using Newcombe method is presented for >0.5 log10 c/mL.
    Comparison groups
    Randomized Cohort-Placebo v Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    45.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    32.95
         upper limit
    55.45
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Difference between treatment groups (fostemsavir 600 mg BID-Placebo) and 95% confidence interval using Newcombe method is presented for >1.0 log10 c/mL.
    Comparison groups
    Randomized Cohort-Placebo v Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    35.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.16
         upper limit
    44.25

    Secondary: Percentage of participants with HIV-1 RNA <40 c/mL at Weeks 24 and 48-Randomized Cohort

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    End point title
    Percentage of participants with HIV-1 RNA <40 c/mL at Weeks 24 and 48-Randomized Cohort
    End point description
    The durability of response (that is, the number of participants achieving HIV-1 RNA <40 c/mL) at Weeks 24 and 48 of open-label fostemsavir plus OBT in the Randomized Cohort was assessed using the Food and Drug Administration (FDA) snapshot algorithm in which participants without HIV-1 RNA at Weeks 24 and 48 or those who changed OBT due to lack of efficacy through Weeks 24 and 48 were counted as failures. The percentage of participants in the Randomized Cohort who achieved virologic success (HIV-1 RNA <40 c/mL) at Weeks 24 and 48 is presented along with 95% Wilson confidence interval. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Weeks 24 and 48
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [8]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 24
    53 (47.0 to 58.8)
        Week 48
    54 (47.7 to 59.5)
    Notes
    [8] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with on-treatment serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation (AELD)-Randomized Cohort

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    End point title
    Number of participants with on-treatment serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation (AELD)-Randomized Cohort
    End point description
    An SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or causes prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; an important medical event that may jeopardize the participant or require intervention. Number of participants with on-treatment SAEs and AEs leading to withdrawal of study treatment is presented. SAEs and AELDs were collected in Safety Population which comprised of all participants who received at least one dose of study treatment. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Up to Week 48 analysis cut-off date
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [9]
    Units: Participants
        SAE
    85
        AELD
    14
    Notes
    [9] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants with toxicity grade increase in clinical chemistry results to Grade 3-4 relative to Baseline-Randomized Cohort

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    End point title
    Number of participants with toxicity grade increase in clinical chemistry results to Grade 3-4 relative to Baseline-Randomized Cohort
    End point description
    Laboratory toxicities were graded for severity according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) grading system: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (potentially life-threatening). Baseline is defined as the latest pre-dose assessment. The number of participants with clinical chemistry toxicity grade increase to Grade 3-4 at anytime post-Baseline relative to Baseline is presented. Only participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 48 analysis cut-off date
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [10]
    Units: Participants
        Albumin; n=268
    1
        Alkaline phosphatase; n=268
    3
        Alanine aminotransferase; n=268
    13
        Amylase; n=268
    2
        Aspartate aminotransferase; n=268
    9
        Bicarbonate; n=268
    1
        Direct bilirubin; n=268
    19
        Bilirubin; n=268
    6
        Calcium; n=268
    9
        Cholesterol; n=221
    10
        Creatine kinase; n=268
    6
        Creatinine; n=268
    43
        Estimated creatinine clearance; n=268
    69
        Glucose/hyperglycemia; n=267
    6
        Glucose/hypoglycemia; n=267
    1
        Potassium/hyperkalemia; n=268
    3
        Potassium/hypokalemia; n=268
    0
        Low density lipoprotein (LDL) cholesterol; n=216
    7
        Lipase; n=268
    12
        Sodium/hypernatremia; n=268
    0
        Sodium/hyponatremia; n=268
    0
        Triglycerides; n=221
    10
        Urate; n=268
    7
    Notes
    [10] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants with toxicity grade increase in hematology results to Grade 3-4 relative to Baseline-Randomized Cohort

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    End point title
    Number of participants with toxicity grade increase in hematology results to Grade 3-4 relative to Baseline-Randomized Cohort
    End point description
    Laboratory toxicities were graded for severity according to the DAIDS grading system: Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (potentially life-threatening). Baseline is defined as the latest pre-dose assessment. The number of participants with hematology toxicity grade increase to Grade 3-4 at anytime post-Baseline relative to Baseline is presented. Only participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 48 analysis cut-off date
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [11]
    Units: Participants
        Hemoglobin; n=268
    14
        Neutrophils; n=268
    8
        Platelets; n=267
    2
        Leukocytes; n=268
    4
    Notes
    [11] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with Centers for Disease Control (CDC) Class C events-Randomized Cohort

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    End point title
    Number of participants with Centers for Disease Control (CDC) Class C events-Randomized Cohort
    End point description
    Disease progression during open label fostemsavir plus OBT was assessed based on the occurrence of new AIDS defining events (CDC Class C events) or death. The number of participants with on-treatment CDC Class C AIDS events is presented. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Up to Week 48 analysis cut-off date
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [12]
    Units: Participants
        Participants
    24
    Notes
    [12] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Day 1 in cluster of differentiation (CD) 4+ T-cell count at Day 8-Randomized Cohort

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    End point title
    Change from Day 1 in cluster of differentiation (CD) 4+ T-cell count at Day 8-Randomized Cohort [13]
    End point description
    CD4+ T- cell counts were assessed by flow cytometry. Mean change in CD4+ T- cell count from Day 1 at Day 8 was analyzed using one-way ANCOVA with change of CD4+ cell counts from Day 1 at Day 8 as the dependent variable, treatment (fostemsavir or placebo) as an in-dependent variable, and Day 1 CD4+ cell count as a continuous covariate. Change from Day 1 was calculated as value at Day 8 minus value at Day 1. Missing CD4+ cell count values at Day 8 were imputed using (a) D1OCF for participants without a value during blinded treatment (i.e., imputing a zero change from Day 1), or (b) LOCF for participants with an early value during blinded treatment before the Day 8 analysis visit window. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 8
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is evaluated only in the Randomized cohort as pre-specified in the protocol and reporting and analysis plan.
    End point values
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects analysed
    69 [14]
    196 [15]
    Units: Cells per cubic millimeter
    least squares mean (confidence interval 95%)
        Cells per cubic millimeter
    18.9 (4.7 to 33.0)
    18.5 (10.1 to 26.8)
    Notes
    [14] - ITT-E Population
    [15] - ITT-E Population
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Difference in covariate-adjusted least squares means between treatment groups (Fostemsavir 600 mg BID-Placebo) is presented.
    Comparison groups
    Randomized Cohort-Placebo v Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.8
         upper limit
    16

    Secondary: Change in CD4+ T- cell count percentage from Day 1 at Day 8-Randomized Cohort

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    End point title
    Change in CD4+ T- cell count percentage from Day 1 at Day 8-Randomized Cohort [16]
    End point description
    CD4+ T- cell counts were assessed by flow cytometry. Mean change in CD4+ T- cell count percentage from Day 1 at Day 8 was analyzed using one-way ANCOVA with change of CD4+ cell count percentage from Day 1 at Day 8 as the dependent variable, treatment (fostemsavir or placebo) as an independent variable, and Day 1 CD4+ cell count percentage as a continuous covariate. Change from Day 1 was calculated as value at Day 8 minus value at Day 1. Missing CD4+ cell count values at Day 8 were imputed using (a) D1OCF for participants without a value during blinded treatment (ie, imputing a zero change from Day 1), or (b) LOCF for participants with an early value during blinded treatment before the Day 8 analysis visit window. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 8
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is evaluated only in the Randomized cohort as pre-specified in the protocol and reporting and analysis plan.
    End point values
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects analysed
    69 [17]
    196 [18]
    Units: Percentage of CD4+T- cells
    least squares mean (confidence interval 95%)
        Percentage of CD4+T- cells
    0.243 (-0.216 to 0.703)
    0.860 (0.588 to 1.133)
    Notes
    [17] - ITT-E Population
    [18] - ITT-E Population
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Difference in covariate-adjusted least squares means between treatment groups (Fostemsavir 600 mg BID-Placebo) is presented.
    Comparison groups
    Randomized Cohort-Placebo v Randomized Cohort-fostemsavir 600 mg BID
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    0.617
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.082
         upper limit
    1.151

    Secondary: Change from Baseline in log10 HIV-1 RNA for fostemsavir when given with OBT through Week 48-Randomized Cohort

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    End point title
    Change from Baseline in log10 HIV-1 RNA for fostemsavir when given with OBT through Week 48-Randomized Cohort
    End point description
    Blood samples were collected for the analysis of HIV-1 RNA. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as the value at post-dose visit minus the value at Baseline. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 48
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [19]
    Units: Log10 c/mL
    arithmetic mean (standard deviation)
        Day 8; n=262
    -0.656 ± 0.7536
        Week 4; n=262
    -2.051 ± 1.0717
        Week 8; n=256
    -2.207 ± 1.1416
        Week 12; n=248
    -2.237 ± 1.2105
        Week 16; n=249
    -2.277 ± 1.2834
        Week 24; n=246
    -2.297 ± 1.2788
        Week 36; n=238
    -2.332 ± 1.2265
        Week 48; n=233
    -2.324 ± 1.2876
    Notes
    [19] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ T- cell count through Week 48-Randomized Cohort

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    End point title
    Change from Baseline in CD4+ T- cell count through Week 48-Randomized Cohort
    End point description
    CD4+ T- cell counts were assessed by flow cytometry. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as the value at post-dose visit minus the value at Baseline. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 48
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [20]
    Units: Cells per cubic millimeter
    arithmetic mean (standard deviation)
        Day 8; n=255
    19.8 ± 60.98
        Week 4; n=259
    48.9 ± 131.75
        Week 8; n=254
    61.5 ± 113.47
        Week 12; n=249
    79.0 ± 123.31
        Week 16; n=245
    84.1 ± 107.26
        Week 24; n=247
    90.4 ± 112.10
        Week 36; n=234
    109.7 ± 119.50
        Week 48; n=228
    138.9 ± 135.06
    Notes
    [20] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in CD4+ T- cell count percentage through Week 48

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    End point title
    Change from Baseline in CD4+ T- cell count percentage through Week 48
    End point description
    CD4+ T- cell counts were assessed by flow cytometry. Baseline is defined as the last non-missing value on or before the date of first dose of study treatment. Change from Baseline was calculated as the value at post-dose visit minus the value at Baseline. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles). All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 48
    End point values
    Randomized cohort
    Number of subjects analysed
    272 [21]
    Units: Percentage of CD4+ T- cells
    arithmetic mean (standard deviation)
        Day 8; n=255
    0.75 ± 1.970
        Week 4; n=259
    2.30 ± 4.643
        Week 8; n=254
    2.36 ± 4.392
        Week 12; n=249
    3.00 ± 4.945
        Week 16; n=245
    3.51 ± 4.979
        Week 24; n=247
    4.26 ± 4.828
        Week 36; n=234
    5.06 ± 5.256
        Week 48; n=228
    6.51 ± 5.531
    Notes
    [21] - ITT-E Population
    No statistical analyses for this end point

    Secondary: Number of participants with treatment-emergent viral genotypic substitution of interest in the GP160 domain as a measure of genotypic resistance-Randomized Cohort

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    End point title
    Number of participants with treatment-emergent viral genotypic substitution of interest in the GP160 domain as a measure of genotypic resistance-Randomized Cohort
    End point description
    Plasma samples were collected for drug resistance testing. Participants with emergent viral genotypic substitutions of interest in GP160 domain was identified by next-generation sequencing (NGS) assay. Virologic failure (VF) Population comprised of all participants with available phenotypic and genotypic resistance data meeting at the time protocol defined virologic failure (PDVF) was met. Criteria for PDVF was a) Confirmed, or last available prior to discontinuation, HIV-1 RNA >=400 c/mL at any time after prior confirmed suppression to <400 c/mL prior to Week 24 or Confirmed, or last available prior to discontinuation, >1 log10 c/mL increase in HIV-1 RNA at any time above nadir level where nadir is >=40 c/mL prior to Week 24. b) Confirmed, or last available prior to discontinuation, HIV-1 RNA >=400 c/mL at or after Week 24. All participants received fostemsavir during open-label period irrespective of original randomization; hence, combined totals for Randomized Cohort is presented.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Randomized cohort
    Number of subjects analysed
    47 [22]
    Units: Participants
        Participants
    20
    Notes
    [22] - VF Population
    No statistical analyses for this end point

    Secondary: Number of participants with indicated fold change ratio (FCR) using the Monogram PhenoSense Entry Assay-Randomized Cohort

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    End point title
    Number of participants with indicated fold change ratio (FCR) using the Monogram PhenoSense Entry Assay-Randomized Cohort
    End point description
    The phenotypic resistance to a drug is defined in terms of a fold change (FC) in IC50, i.e., the ratio of the 50% inhibitory concentration (IC50) of the clinical isolate to the IC50 of a reference strain (wild type control). FCR was calculated as FC at PDVF divided by Baseline FC. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. FCR<1 indicates that FC is smaller on-treatment than at Baseline. FCR >3 indicates that on-treatment FC is 3 times greater than it was at Baseline. Only participants available at the specified time point were analyzed. All the participants received fostemsavir during the open-label period irrespective of the original arms to which they were randomized; hence, the combined totals for Randomized Cohort is presented as pre-specified in protocol and reporting and analysis plan.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Randomized cohort
    Number of subjects analysed
    44 [23]
    Units: Participants
        <=1
    15
        >1 to 3
    8
        >3 to 10
    4
        >10 to 100
    1
        >100 to 3000
    9
        >3000
    7
    Notes
    [23] - VF Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment non-SAEs and SAEs were collected from start of study treatment until Week 48 data cut-off date. For Randomized Cohort-Placebo and Randomized Cohort-fostemsavir 600 mg BID, non-SAEs and SAEs during double-blind period (upto Day8) is presented.
    Adverse event reporting additional description
    Non-SAEs and SAEs were collected in the Safety Population which comprised of all participants who received at least one dose of study treatment. One participant was excluded from the Total fostemsavir population as the participant took only placebo and had discontinued during the double-blind period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Randomized Cohort-Placebo
    Reporting group description
    This reporting group includes HTE HIV-1 infected participants who were assigned to the Randomized Cohort and randomized to placebo twice daily (BID) along with their currently failing antiretroviral regimen for the double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID and an optimized background therapy (OBT). Randomized Cohort participants are assigned based on their screening status of having <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen. The data reported are safety events during the 8-day double-blind period.

    Reporting group title
    Randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    This reporting group includes HTE HIV-1 infected participants who were assigned to the Randomized Cohort and randomized to fostemsavir 600 mg BID along with their currently failing antiretroviral regimen for the double-blind period. During the open-label period, all participants received fostemsavir 600 mg BID and OBT. Randomized Cohort participants are assigned based on their screening status of having <=2 classes of antiretrovirals remaining with at least 1 but no more than 2 remaining fully active antiretrovirals that can be effectively combined to form a viable new regimen. The data reported are safety events during the 8-day double-blind period.

    Reporting group title
    Randomized Cohort-Total
    Reporting group description
    This reporting group includes all participants in the Randomized Cohort. The data reported are safety events during fostemsavir dosing until the Week 48 data cut-off date.

    Reporting group title
    Non-randomized Cohort-fostemsavir 600 mg BID
    Reporting group description
    This reporting group includes HTE HIV-1 infected participants who were assigned to the Non-randomized Cohort and received fostemsavir 600 mg BID and OBT. Non-randomized Cohort participants are assigned based on their screening status of having no remaining classes of fully active antiretroviral that can combined in a new drug regimen. The data reported are safety events during fostemsavir dosing until the Week 48 data cut-off date.

    Reporting group title
    Total fostemsavir
    Reporting group description
    This reporting group included all enrolled participants (Randomized Cohort and Non-randomized Cohort) and who received fostemsavir 600 mg during the open-label period. The data reported are safety events during fostemsavir dosing until the Week 48 data cut-off date.

    Serious adverse events
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID Randomized Cohort-Total Non-randomized Cohort-fostemsavir 600 mg BID Total fostemsavir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 69 (2.90%)
    5 / 203 (2.46%)
    85 / 271 (31.37%)
    44 / 99 (44.44%)
    129 / 370 (34.86%)
         number of deaths (all causes)
    1
    1
    10
    14
    24
         number of deaths resulting from adverse events
    1
    1
    9
    12
    21
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    2 / 99 (2.02%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    3 / 271 (1.11%)
    1 / 99 (1.01%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Anal squamous cell carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    2 / 99 (2.02%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal cancer metastatic
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma recurrent
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Keratoacanthoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage IV
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Uterine leiomyoma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    2 / 271 (0.74%)
    1 / 99 (1.01%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
    Hypersensitivity
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal growth restriction
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    2 / 99 (2.02%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adverse event
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    0 / 99 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial bypass thrombosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Open fracture
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood HIV RNA increased
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    3 / 271 (1.11%)
    0 / 99 (0.00%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    0 / 99 (0.00%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    2 / 99 (2.02%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mononeuropathy
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    4 / 271 (1.48%)
    0 / 99 (0.00%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    0 / 99 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anogenital dysplasia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malabsorption
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reactive gastropathy
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    3 / 99 (3.03%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    2 / 99 (2.02%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    0 / 99 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    2 / 99 (2.02%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    Cholecystitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    0 / 99 (0.00%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 203 (0.99%)
    12 / 271 (4.43%)
    3 / 99 (3.03%)
    15 / 370 (4.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 14
    0 / 4
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    5 / 271 (1.85%)
    3 / 99 (3.03%)
    8 / 370 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    3 / 271 (1.11%)
    1 / 99 (1.01%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    3 / 99 (3.03%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    3 / 99 (3.03%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    Chronic sinusitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    1 / 99 (1.01%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    2 / 99 (2.02%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    2 / 271 (0.74%)
    0 / 99 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIV-associated neurocognitive disorder
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    0 / 99 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    0 / 99 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    1 / 99 (1.01%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Abdominal wall abscess
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal cellulitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Bacterial sepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated cytomegaloviral infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B reactivation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis disseminated
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis coccidioides
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningoencephalitis viral
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Orchitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonella bacteraemia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic rash
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis liver
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    0 / 99 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    0 / 271 (0.00%)
    1 / 99 (1.01%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Randomized Cohort-Placebo Randomized Cohort-fostemsavir 600 mg BID Randomized Cohort-Total Non-randomized Cohort-fostemsavir 600 mg BID Total fostemsavir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 69 (23.19%)
    48 / 203 (23.65%)
    207 / 271 (76.38%)
    89 / 99 (89.90%)
    296 / 370 (80.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    10 / 271 (3.69%)
    7 / 99 (7.07%)
    17 / 370 (4.59%)
         occurrences all number
    0
    0
    12
    8
    20
    Skin papilloma
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    6 / 271 (2.21%)
    5 / 99 (5.05%)
    11 / 370 (2.97%)
         occurrences all number
    0
    0
    6
    6
    12
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    1 / 271 (0.37%)
    5 / 99 (5.05%)
    6 / 370 (1.62%)
         occurrences all number
    0
    0
    1
    5
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 203 (0.00%)
    32 / 271 (11.81%)
    10 / 99 (10.10%)
    42 / 370 (11.35%)
         occurrences all number
    1
    0
    41
    11
    52
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 69 (7.25%)
    8 / 203 (3.94%)
    34 / 271 (12.55%)
    11 / 99 (11.11%)
    45 / 370 (12.16%)
         occurrences all number
    5
    8
    50
    12
    62
    Dizziness
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 203 (0.99%)
    15 / 271 (5.54%)
    5 / 99 (5.05%)
    20 / 370 (5.41%)
         occurrences all number
    1
    2
    15
    5
    20
    Neuropathy peripheral
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    6 / 271 (2.21%)
    5 / 99 (5.05%)
    11 / 370 (2.97%)
         occurrences all number
    0
    1
    7
    5
    12
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 203 (0.49%)
    24 / 271 (8.86%)
    16 / 99 (16.16%)
    40 / 370 (10.81%)
         occurrences all number
    1
    1
    36
    23
    59
    Fatigue
         subjects affected / exposed
    3 / 69 (4.35%)
    3 / 203 (1.48%)
    17 / 271 (6.27%)
    16 / 99 (16.16%)
    33 / 370 (8.92%)
         occurrences all number
    3
    3
    18
    16
    34
    Asthenia
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 203 (0.99%)
    11 / 271 (4.06%)
    12 / 99 (12.12%)
    23 / 370 (6.22%)
         occurrences all number
    2
    2
    12
    12
    24
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    16 / 271 (5.90%)
    3 / 99 (3.03%)
    19 / 370 (5.14%)
         occurrences all number
    0
    0
    17
    3
    20
    Insomnia
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 203 (0.99%)
    16 / 271 (5.90%)
    3 / 99 (3.03%)
    19 / 370 (5.14%)
         occurrences all number
    1
    2
    17
    3
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 69 (4.35%)
    11 / 203 (5.42%)
    58 / 271 (21.40%)
    24 / 99 (24.24%)
    82 / 370 (22.16%)
         occurrences all number
    3
    11
    79
    43
    122
    Nausea
         subjects affected / exposed
    4 / 69 (5.80%)
    15 / 203 (7.39%)
    40 / 271 (14.76%)
    20 / 99 (20.20%)
    60 / 370 (16.22%)
         occurrences all number
    4
    15
    60
    28
    88
    Vomiting
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 203 (0.99%)
    28 / 271 (10.33%)
    9 / 99 (9.09%)
    37 / 370 (10.00%)
         occurrences all number
    0
    2
    44
    12
    56
    Abdominal pain
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 203 (1.48%)
    22 / 271 (8.12%)
    4 / 99 (4.04%)
    26 / 370 (7.03%)
         occurrences all number
    0
    3
    30
    4
    34
    Constipation
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 203 (1.48%)
    20 / 271 (7.38%)
    6 / 99 (6.06%)
    26 / 370 (7.03%)
         occurrences all number
    0
    3
    20
    7
    27
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    8 / 271 (2.95%)
    5 / 99 (5.05%)
    13 / 370 (3.51%)
         occurrences all number
    0
    0
    15
    6
    21
    Pruritus
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    6 / 271 (2.21%)
    5 / 99 (5.05%)
    11 / 370 (2.97%)
         occurrences all number
    0
    1
    6
    8
    14
    Eczema
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    5 / 271 (1.85%)
    5 / 99 (5.05%)
    10 / 370 (2.70%)
         occurrences all number
    0
    0
    5
    5
    10
    Night sweats
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    2 / 271 (0.74%)
    5 / 99 (5.05%)
    7 / 370 (1.89%)
         occurrences all number
    0
    0
    15
    5
    20
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    20 / 271 (7.38%)
    8 / 99 (8.08%)
    28 / 370 (7.57%)
         occurrences all number
    0
    0
    22
    9
    31
    Back pain
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 203 (0.00%)
    15 / 271 (5.54%)
    13 / 99 (13.13%)
    28 / 370 (7.57%)
         occurrences all number
    1
    0
    17
    16
    33
    Pain in extremity
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    13 / 271 (4.80%)
    6 / 99 (6.06%)
    19 / 370 (5.14%)
         occurrences all number
    0
    0
    15
    6
    21
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    5 / 271 (1.85%)
    8 / 99 (8.08%)
    13 / 370 (3.51%)
         occurrences all number
    0
    0
    5
    9
    14
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    37 / 271 (13.65%)
    13 / 99 (13.13%)
    50 / 370 (13.51%)
         occurrences all number
    0
    1
    52
    17
    69
    Nasopharyngitis
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 203 (0.99%)
    27 / 271 (9.96%)
    16 / 99 (16.16%)
    43 / 370 (11.62%)
         occurrences all number
    0
    2
    39
    22
    61
    Influenza
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    25 / 271 (9.23%)
    13 / 99 (13.13%)
    38 / 370 (10.27%)
         occurrences all number
    0
    1
    29
    15
    44
    Bronchitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    28 / 271 (10.33%)
    5 / 99 (5.05%)
    33 / 370 (8.92%)
         occurrences all number
    0
    0
    35
    6
    41
    Sinusitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    19 / 271 (7.01%)
    9 / 99 (9.09%)
    28 / 370 (7.57%)
         occurrences all number
    0
    0
    24
    9
    33
    Urinary tract infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    13 / 271 (4.80%)
    10 / 99 (10.10%)
    23 / 370 (6.22%)
         occurrences all number
    0
    0
    15
    12
    27
    Oral candidiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    15 / 271 (5.54%)
    7 / 99 (7.07%)
    22 / 370 (5.95%)
         occurrences all number
    0
    1
    18
    8
    26
    Gastroenteritis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 203 (0.49%)
    9 / 271 (3.32%)
    6 / 99 (6.06%)
    15 / 370 (4.05%)
         occurrences all number
    0
    1
    9
    6
    15
    Oral herpes
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 203 (0.00%)
    5 / 271 (1.85%)
    5 / 99 (5.05%)
    10 / 370 (2.70%)
         occurrences all number
    0
    0
    5
    5
    10

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2015
    - Clarify in the protocol that the study will be 96 weeks in duration. - Update with new drug-drug interaction information. - Update with contraception changes. - Update with new Division of AIDS (DAIDS) information for 2014. - Add minor administrative changes.
    04 Feb 2016
    - Clarify the timing of database locks for interim and final analysis of study data, to clarify statistical methods of analysis, and to further define populations for analysis. - Update the anticipated sample size of the randomized and non-randomized cohorts as well as the overall treated population. - Clarify the contraception requirements for Women of Childbearing Potential interested in being treated in the current study. - Updated the list of prohibited concomitant medications. - Updated the names and contact information of the study’s medical monitor and study director. - Other minor edits were made to improve the readability of the document.
    17 Aug 2016
    - Identify ViiV Healthcare Company as the sponsor of the study and removed references to Bristol-Myers Squibb (BMS) as the sponsor. - Acknowledge that GlaxoSmithKline (GSK) and Pharmaceutical Product Development (PPD) are supporting ViiV Healthcare in the conduct of the study. - Include the GSK compound number (GSK3684934) and metabolite number (GSK2616713). - Include the GSK study number (205888). - Indicate that molecular analysis will occur at ViiV Healthcare Discovery (Wallingford, CT, USA) instead of at BMS. - Allow study treatment beyond 96 weeks. - Update the endpoints to include a reference to the previously planned interim analysis at Week 48. - Add an interim analysis after the last participant (randomized or non-randomized) completes the Week 96 visit. - Remove InCell Dx sampling at all visits except Screening. - Temporary change in the participant visit schedule to receive study medication every 4 weeks. - Other minor edits were made to improve the readability of the document.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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