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    Clinical Trial Results:
    AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    2009-011150-17
    Trial protocol
    NL   ES   BE   SE   GB   AT   GR   DE   IT   FR  
    Global end of trial date
    31 Jul 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    08 Apr 2016
    First version publication date
    10 Apr 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Changes required to the EudraCT Results Summary in order to keep consistent with the changes made to the FDAAA Results Summary per the NIH QC review.

    Trial information

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    Trial identification
    Sponsor protocol code
    AMB112565
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the difference between two treatment strategies; first-line combination therapy (with ambrisentan 10 mg once daily and tadalafil 40 mg once daily) vs. monotherapy (with ambrisentan 10 mg once daily or tadalafil 40 mg once daily) in participants with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    A gradual titration was put in place in the study, with full dose of tadalafil reached at week 4 and ambrisentan at week 8 – this was intended to minimize the potential for side effects in participants receiving combination therapy.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Sweden: 21
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 48
    Country: Number of subjects enrolled
    Germany: 96
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 29
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    United States: 248
    Worldwide total number of subjects
    610
    EEA total number of subjects
    318
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    403
    From 65 to 84 years
    207
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    500 participants (par.) in the ITT Population were also included in the modified ITT Population (those who also met the modified inclusion/exclusion criteria defined in the protocol amendment 2). Disposition results below have been presented for the ITT Population.

    Pre-assignment
    Screening details
    A total of 610 par. were randomized; however, only 605 were included in the Intent-to-Treat (ITT) Population (randomized par. who received at least one dose of IP). All par. received a minimum of 24 weeks of therapy unless they died or withdrew.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Combination Therapy: Ambrisentan + Tadalafil
    Arm description
    Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    ambrisentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg or 10 mg, once-daily, oral

    Investigational medicinal product name
    tadalafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg or 40 mg once-daily, oral

    Arm title
    Ambrisentan Monotherapy
    Arm description
    Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.
    Arm type
    Active comparator

    Investigational medicinal product name
    ambrisentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg or 10 mg, once-daily, oral

    Arm title
    Tadalafil Monotherapy
    Arm description
    Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    tadalafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg or 40 mg once-daily, oral

    Number of subjects in period 1 [1]
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy
    Started
    302
    152
    151
    Completed
    240
    108
    105
    Not completed
    62
    44
    46
         Protocol deviation
             1
             1
             1
         Physician decision
             14
             10
             10
         Adverse event, serious fatal
             9
             15
             17
         Adverse event, non-fatal
             25
             12
             7
         Consent withdrawn by subject
             10
             6
             8
         Missing Completion Status
             1
             -
             -
         Lost to follow-up
             2
             -
             3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 610 participants (par.) were randomized; however, only 605 were included in the Intent-to-Treat (ITT) Population (randomized participants who received at least one dose of IP).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Combination Therapy: Ambrisentan + Tadalafil
    Reporting group description
    Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Reporting group title
    Ambrisentan Monotherapy
    Reporting group description
    Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Reporting group title
    Tadalafil Monotherapy
    Reporting group description
    Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.

    Reporting group values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Total
    Number of subjects
    302 152 151 605
    Age categorical
    Units: Subjects
    Age continuous
    Intent-to-Treat Population
    Units: years
        arithmetic mean (standard deviation)
    55.9 ± 13.86 55.2 ± 14.41 55.9 ± 14.75 -
    Gender categorical
    Units: Subjects
        Female
    223 117 121 461
        Male
    79 35 30 144
    Race
    Units: Subjects
        African American/African Heritage
    11 14 13 38
        American Indian or Alaskan Native
    2 0 0 2
        Asian - Central/South Asian Heritage
    1 2 1 4
        Asian - Japanese Heritage
    3 0 1 4
        Asian - South East Asian Heritage
    1 2 1 4
        Native Hawaiian or Other Pacific Islander
    1 0 2 3
        White - Arabic /North African Heritage
    1 1 0 2
        White - White/Caucasian/European Heritage
    280 131 133 544
        Mixed Race
    2 1 0 3
        Missing
    0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Combination Therapy: Ambrisentan + Tadalafil
    Reporting group description
    Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Reporting group title
    Ambrisentan Monotherapy
    Reporting group description
    Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Reporting group title
    Tadalafil Monotherapy
    Reporting group description
    Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.

    Subject analysis set title
    Monotherapy Pooled: Ambrisentan or Tadalafil
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Primary: Number of participants with first adjudicated clinical failure (CF) event, death, hospitalisation for worsening PAH, disease progression, unsatisfactory long-term clinical response, all through FAV

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    End point title
    Number of participants with first adjudicated clinical failure (CF) event, death, hospitalisation for worsening PAH, disease progression, unsatisfactory long-term clinical response, all through FAV
    End point description
    Time to the first adjudicated CF event (death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) after initiating either first-line combination therapy with AMB and TAD or first-line monotherapy with either drug (AMB or TAD) in par. with PAH was assessed. If data was not available for some par. following a loss to follow-up, their event times were treated as censored at their last assessment time for the statistical analyses. FAV occurred approximately 4 weeks after the predicted 105th adjudicated first CF event was reached. Par. who had an FAV, and who had no adjudicated events or whose first adjudicated event occurred after their FAV, were censored at their individual FAV. Modified Intent-to-Treat (mITT) Population: all randomized par. who met the PAH diagnosis and inclusion/exclusion criteria defined in protocol amendment 2 and who also received at least one dose of investigational product (IP).
    End point type
    Primary
    End point timeframe
    From Baseline up to the Final Assessment Visit (FAV) (average of 609 days)
    End point values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects analysed
    253 [1]
    126 [2]
    121 [3]
    247 [4]
    Units: Participants
        First adjudicated clinical failure event
    46
    43
    34
    77
        Death (all-cause)
    9
    2
    6
    8
        Hospitalization for worsening PAH
    10
    18
    12
    30
        Disease progression
    10
    12
    4
    16
        Unsatisfactory long-term clinical response
    17
    11
    12
    23
    Notes
    [1] - mITT Population
    [2] - mITT Population
    [3] - mITT Population
    [4] - mITT Population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0002
    Method
    Stratified Log Rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.502
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.348
         upper limit
    0.724
    Notes
    [5] - Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Monotherapy Pooled: Ambrisentan or Tadalafil.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Ambrisentan Monotherapy
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.0004
    Method
    Stratified Log Rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.477
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.314
         upper limit
    0.723
    Notes
    [6] - Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Ambrisentan Monotherapy.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Tadalafil Monotherapy
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0045
    Method
    Stratified Log Rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.528
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.338
         upper limit
    0.827
    Notes
    [7] - Analysis of time to first adjudicated clinical failure event through FAV. HR is calculated using the Cox proportional hazards model. HR is for Combination Therapy: Ambrisentan + Tadalafil / Tadalafil Monotherapy.

    Secondary: Percent change from Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24

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    End point title
    Percent change from Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Week 24
    End point description
    N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate marker of heart failure. The data were log-transformed. The geometric mean was calculated (based on the log-transformed data). The geometric mean ratio was calculated as the ratio between the Week 24 value and the Baseline value (based on the log-transformed data) and presented as percent change = 100 * (geometric mean ratio – 1). The Baseline value is the last value prior to administration of study drug; this may be prior to or on the day of study drug initiation. No imputation was performed for missing data. The secondary endpoints were analyzed according to a pre-specified hierarchical testing procedure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects analysed
    204 [8]
    126 [9]
    121 [10]
    247 [11]
    Units: Percent change
        arithmetic mean (standard error)
    -67.15 ± 0.069
    -50.37 ± 0.07
    -56.15 ± 0.096
    -43.83 ± 0.095
    Notes
    [8] - mITT Population. Only participants with data available at the specified time points were analyzed.
    [9] - mITT Population. Only participants with data available at the specified time points were analyzed.
    [10] - mITT Population. Only participants with data available at the specified time points were analyzed.
    [11] - mITT Population. Only participants with data available at the specified time points were analyzed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean Percent Difference
    Point estimate
    -33.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -44.78
         upper limit
    -20.66
    Notes
    [12] - Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Ambrisentan Monotherapy
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.0111
    Method
    ANCOVA
    Parameter type
    Mean Percent Difference
    Point estimate
    -25.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.04
         upper limit
    -6.4
    Notes
    [13] - Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Tadalafil Monotherapy
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean Percent Difference
    Point estimate
    -41.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -53.16
         upper limit
    -26.97
    Notes
    [14] - Mean percent difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

    Secondary: Percentage of participants with a satisfactory clinical response at Week 24

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    End point title
    Percentage of participants with a satisfactory clinical response at Week 24
    End point description
    A satisfactory clinical response at Week 24 is defined as a participant who meets all of the following criteria: 10% improvement in 6MWD compared with Baseline; improvement to or maintenance of World Health Organization (WHO) class I or II symptoms; no events of clinical worsening prior to or at the Week 24 visit. Clinical worsening events included: death, hospitalization for pulmonary arterial hypertension (PAH), and disease progression. Participants without an event of clinical worsening prior to or at the Week 24 visit who did not have a 6MWD value or a WHO functional class value at Week 24 were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects analysed
    234 [15]
    113 [16]
    113 [17]
    226 [18]
    Notes
    [15] - mITT Population. Only those participants who had a "Yes"/"No" response were analyzed.
    [16] - mITT Population. Only those participants who had a "Yes"/"No" response were analyzed.
    [17] - mITT Population. Only those participants who had a "Yes"/"No" response were analyzed.
    [18] - mITT Population. Only those participants who had a "Yes"/"No" response were analyzed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects included in analysis
    460
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0264
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.563
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.054
         upper limit
    2.319
    Notes
    [19] - Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Monotherapy Pooled: Ambrisentan or Tadalafil.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Ambrisentan Monotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    P-value
    = 0.1518
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.424
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.878
         upper limit
    2.308
    Notes
    [20] - Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Ambrisentan Monotherapy.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Tadalafil Monotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0321
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.723
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.047
         upper limit
    2.833
    Notes
    [21] - Odds ratio is for Combination Therapy: Ambrisentan + Tadalafil / Tadalafil Monotherapy.

    Secondary: Change from Baseline in the 6 minute walk distance test at Week 24

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    End point title
    Change from Baseline in the 6 minute walk distance test at Week 24
    End point description
    The 6-minute walk distance (6MWD) test measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned a rank reflecting the relative order of the actual event times. Baseline 6MWD comprised of an average of the last two consecutive measurements prior to randomization that varied by no greater than 10%. If only one measurement was available, that measurement was used. If no two consecutive measures vary by no greater than 10% then Baseline was based on the last two consecutive measures for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects analysed
    248 [22]
    124 [23]
    120 [24]
    244 [25]
    Units: Meters
        median (confidence interval 95%)
    48.98 (39 to 57.5)
    27 (12.5 to 38)
    22.7 (16.5 to 35.5)
    23.8 (19 to 33.5)
    Notes
    [22] - mITT Population. Only participants with Baseline data were analyzed.
    [23] - mITT Population. Only participants with Baseline data were analyzed.
    [24] - mITT Population. Only participants with Baseline data were analyzed.
    [25] - mITT Population. Only participants with Baseline data were analyzed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    < 0.0001
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    22.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12
         upper limit
    33.5
    Notes
    [26] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Ambrisentan Monotherapy
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    = 0.0005
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    24.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11
         upper limit
    38.5
    Notes
    [27] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Tadalafil Monotherapy
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.003
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    20.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8
         upper limit
    33.7
    Notes
    [28] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

    Secondary: Change from Baseline in the World Health Organization Functional Class at Week 24

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    End point title
    Change from Baseline in the World Health Organization Functional Class at Week 24
    End point description
    The WHO Functional Class (FC) indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). Baseline WHO FC is the latest assessment prior to dosing (i.e., at Randomization or Screening). Change from Baseline at Week 24 was calculated as the Week 24 value minus the Baseline value. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observations was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects analysed
    252 [29]
    124 [30]
    120 [31]
    244 [32]
    Units: Scores on a scale
        median (inter-quartile range (Q1-Q3))
    0 (-1 to 0)
    0 (-1 to 0)
    0 (-1 to 0)
    0 (-1 to 0)
    Notes
    [29] - mITT Population. Only participants with Baseline data were analyzed.
    [30] - mITT Population. Only participants with Baseline data were analyzed.
    [31] - mITT Population. Only participants with Baseline data were analyzed.
    [32] - mITT Population. Only participants with Baseline data were analyzed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.2287
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0
    Notes
    [33] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    This comparison was not formally tested according to the pre-defined hierarchical testing procedure.
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Ambrisentan Monotherapy
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0
    Notes
    [34] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    This comparison was not formally tested according to the pre-defined hierarchical testing procedure.
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Tadalafil Monotherapy
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0
    Notes
    [35] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

    Secondary: Change from Baseline in Borg Dyspnea Index at Week 24

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    End point title
    Change from Baseline in Borg Dyspnea Index at Week 24
    End point description
    Borg Dyspnea Index (BDI) indicates the degree of breathlessness after completion of the 6 minute walk test. The BDI was calculated by using the Borg category (C) ratio (R) CR10 scale which starts at 0 (nothing at all) and has no upper limit (extremely strong). Change from BL was calculated as the Week 24 values minus the BL value. The BDI scale was assessed by each participant. The BL BDI score is the average of the two BDI values obtained following the two 6MWD tests used in determining the BL 6MWD. A negative change from BL in the BDI score represented an improvement for the participant. The analysis was performed based on the last observation carried forward data, except in the case of an adjudicated clinical failure event of death or hospitalization preceding the missing data observation. In this case, the missing observation was assigned the worst-rank score relative to those actually observed and was assigned rank reflecting the relative order of the actual event times.
    End point type
    Secondary
    End point timeframe
    Baseline (BL) and Week 24
    End point values
    Combination Therapy: Ambrisentan + Tadalafil Ambrisentan Monotherapy Tadalafil Monotherapy Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects analysed
    247 [36]
    124 [37]
    120 [38]
    244 [39]
    Units: Scores on a scale
        median (inter-quartile range (Q1-Q3))
    -1 (-2 to 0.5)
    -0.5 (-1.5 to 0.5)
    -0.5 (-2 to 0.88)
    -0.5 (-1.5 to 0.5)
    Notes
    [36] - mITT Population. Only participants with Baseline data were analyzed.
    [37] - mITT Population. Only participants with Baseline data were analyzed.
    [38] - mITT Population. Only participants with Baseline data were analyzed.
    [39] - mITT Population. Only participants with Baseline data were analyzed.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Monotherapy Pooled: Ambrisentan or Tadalafil
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    0
    Notes
    [40] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Monotherapy Pooled: Ambrisentan or Tadalafil.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Ambrisentan Monotherapy
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0
    Notes
    [41] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Ambrisentan Monotherapy.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    This endpoint was not formally tested according to the pre-defined hierarchical testing procedure.
    Comparison groups
    Combination Therapy: Ambrisentan + Tadalafil v Tadalafil Monotherapy
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    Method
    Stratified Wilcoxon Rank Sum Test
    Parameter type
    Median Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0
    Notes
    [42] - Median difference is for Combination Therapy: Ambrisentan + Tadalafil - Tadalafil Monotherapy.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from the start of investigational product until 30 days after the last dose of investigational product (average of 639 days on investigational product).
    Adverse event reporting additional description
    SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of investigational product. Only AEs for the “On-Randomized Treatment” arms are tabulated.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Combination Therapy: Ambrisentan + Tadalafil
    Reporting group description
    Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Reporting group title
    Tadalafil Monotherapy
    Reporting group description
    Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.

    Reporting group title
    Ambrisentan Monotherapy
    Reporting group description
    Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.

    Serious adverse events
    Combination Therapy: Ambrisentan + Tadalafil Tadalafil Monotherapy Ambrisentan Monotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 302 (41.06%)
    68 / 151 (45.03%)
    63 / 152 (41.45%)
         number of deaths (all causes)
    29
    22
    19
         number of deaths resulting from adverse events
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 302 (0.99%)
    2 / 151 (1.32%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian artery stenosis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular insufficiency
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of the cervix
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pancreatic carcinoma stage IV
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland neoplasm
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 302 (0.00%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Euthanasia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion site phlebitis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 302 (2.32%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    5 / 302 (1.66%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 302 (1.32%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mountain sickness acute
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural myocardial infarction
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic ulcer
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 302 (0.33%)
    3 / 151 (1.99%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 302 (0.99%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 302 (0.66%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    6 / 302 (1.99%)
    3 / 151 (1.99%)
    6 / 152 (3.95%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 302 (0.99%)
    1 / 151 (0.66%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiorenal syndrome
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale acute
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nodal arrhythmia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    5 / 302 (1.66%)
    3 / 151 (1.99%)
    8 / 152 (5.26%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 302 (0.00%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 302 (0.99%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 302 (3.31%)
    4 / 151 (2.65%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    3 / 10
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 302 (0.66%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 302 (1.32%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    2 / 302 (0.66%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 302 (0.99%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 302 (0.00%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    11 / 302 (3.64%)
    12 / 151 (7.95%)
    16 / 152 (10.53%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
    0 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Pulmonary oedema
         subjects affected / exposed
    4 / 302 (1.32%)
    0 / 151 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary vasculitis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 302 (1.66%)
    1 / 151 (0.66%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 302 (3.31%)
    5 / 151 (3.31%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    1 / 12
    2 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperchromic anaemia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    9 / 302 (2.98%)
    7 / 151 (4.64%)
    5 / 152 (3.29%)
         occurrences causally related to treatment / all
    4 / 10
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenogastric reflux
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiploic appendagitis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 302 (0.99%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 302 (0.33%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 302 (0.66%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 302 (0.66%)
    1 / 151 (0.66%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    3 / 302 (0.99%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chondromalacia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Connective tissue disorder
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Juvenile idiopathic arthritis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mixed connective tissue disease
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic sclerosis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    5 / 302 (1.66%)
    4 / 151 (2.65%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    3 / 302 (0.99%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic syndrome
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alveolar osteitis
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 302 (0.33%)
    3 / 151 (1.99%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 302 (0.66%)
    3 / 151 (1.99%)
    5 / 152 (3.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis viral
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 302 (0.66%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 302 (0.33%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 302 (0.99%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    15 / 302 (4.97%)
    7 / 151 (4.64%)
    10 / 152 (6.58%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 8
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    4 / 302 (1.32%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 302 (0.33%)
    3 / 151 (1.99%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 302 (0.33%)
    2 / 151 (1.32%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 302 (0.66%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 302 (0.33%)
    0 / 151 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    West Nile viral infection
         subjects affected / exposed
    0 / 302 (0.00%)
    0 / 151 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 302 (0.00%)
    1 / 151 (0.66%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Combination Therapy: Ambrisentan + Tadalafil Tadalafil Monotherapy Ambrisentan Monotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    279 / 302 (92.38%)
    135 / 151 (89.40%)
    140 / 152 (92.11%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    41 / 302 (13.58%)
    15 / 151 (9.93%)
    18 / 152 (11.84%)
         occurrences all number
    44
    16
    18
    Hypotension
         subjects affected / exposed
    21 / 302 (6.95%)
    9 / 151 (5.96%)
    8 / 152 (5.26%)
         occurrences all number
    25
    10
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 302 (2.98%)
    8 / 151 (5.30%)
    4 / 152 (2.63%)
         occurrences all number
    9
    8
    4
    Chest discomfort
         subjects affected / exposed
    16 / 302 (5.30%)
    5 / 151 (3.31%)
    6 / 152 (3.95%)
         occurrences all number
    18
    6
    6
    Fatigue
         subjects affected / exposed
    35 / 302 (11.59%)
    20 / 151 (13.25%)
    22 / 152 (14.47%)
         occurrences all number
    42
    22
    26
    Non-cardiac chest pain
         subjects affected / exposed
    26 / 302 (8.61%)
    9 / 151 (5.96%)
    14 / 152 (9.21%)
         occurrences all number
    31
    9
    17
    Oedema peripheral
         subjects affected / exposed
    133 / 302 (44.04%)
    44 / 151 (29.14%)
    60 / 152 (39.47%)
         occurrences all number
    184
    55
    82
    Pain
         subjects affected / exposed
    8 / 302 (2.65%)
    8 / 151 (5.30%)
    2 / 152 (1.32%)
         occurrences all number
    8
    8
    2
    Pyrexia
         subjects affected / exposed
    17 / 302 (5.63%)
    2 / 151 (1.32%)
    6 / 152 (3.95%)
         occurrences all number
    22
    2
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    13 / 302 (4.30%)
    8 / 151 (5.30%)
    3 / 152 (1.97%)
         occurrences all number
    15
    8
    3
    Insomnia
         subjects affected / exposed
    21 / 302 (6.95%)
    10 / 151 (6.62%)
    6 / 152 (3.95%)
         occurrences all number
    23
    11
    7
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    33 / 302 (10.93%)
    20 / 151 (13.25%)
    22 / 152 (14.47%)
         occurrences all number
    40
    20
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    38 / 302 (12.58%)
    11 / 151 (7.28%)
    8 / 152 (5.26%)
         occurrences all number
    39
    12
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    53 / 302 (17.55%)
    25 / 151 (16.56%)
    20 / 152 (13.16%)
         occurrences all number
    62
    28
    25
    Dyspnoea
         subjects affected / exposed
    46 / 302 (15.23%)
    28 / 151 (18.54%)
    27 / 152 (17.76%)
         occurrences all number
    61
    39
    32
    Epistaxis
         subjects affected / exposed
    27 / 302 (8.94%)
    15 / 151 (9.93%)
    7 / 152 (4.61%)
         occurrences all number
    32
    18
    7
    Nasal congestion
         subjects affected / exposed
    58 / 302 (19.21%)
    17 / 151 (11.26%)
    25 / 152 (16.45%)
         occurrences all number
    69
    20
    34
    Oropharyngeal pain
         subjects affected / exposed
    7 / 302 (2.32%)
    9 / 151 (5.96%)
    9 / 152 (5.92%)
         occurrences all number
    9
    11
    9
    Sinus congestion
         subjects affected / exposed
    18 / 302 (5.96%)
    4 / 151 (2.65%)
    9 / 152 (5.92%)
         occurrences all number
    19
    5
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    62 / 302 (20.53%)
    22 / 151 (14.57%)
    31 / 152 (20.39%)
         occurrences all number
    71
    29
    35
    Headache
         subjects affected / exposed
    124 / 302 (41.06%)
    55 / 151 (36.42%)
    51 / 152 (33.55%)
         occurrences all number
    149
    69
    69
    Presyncope
         subjects affected / exposed
    11 / 302 (3.64%)
    11 / 151 (7.28%)
    6 / 152 (3.95%)
         occurrences all number
    12
    12
    6
    Syncope
         subjects affected / exposed
    9 / 302 (2.98%)
    8 / 151 (5.30%)
    4 / 152 (2.63%)
         occurrences all number
    11
    9
    7
    Eye disorders
    Vision blurred
         subjects affected / exposed
    19 / 302 (6.29%)
    4 / 151 (2.65%)
    8 / 152 (5.26%)
         occurrences all number
    20
    4
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 302 (1.66%)
    8 / 151 (5.30%)
    6 / 152 (3.95%)
         occurrences all number
    5
    10
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 302 (1.32%)
    11 / 151 (7.28%)
    8 / 152 (5.26%)
         occurrences all number
    4
    13
    8
    Abdominal pain
         subjects affected / exposed
    9 / 302 (2.98%)
    7 / 151 (4.64%)
    9 / 152 (5.92%)
         occurrences all number
    9
    10
    9
    Abdominal pain upper
         subjects affected / exposed
    8 / 302 (2.65%)
    8 / 151 (5.30%)
    6 / 152 (3.95%)
         occurrences all number
    8
    8
    8
    Constipation
         subjects affected / exposed
    17 / 302 (5.63%)
    6 / 151 (3.97%)
    10 / 152 (6.58%)
         occurrences all number
    20
    6
    11
    Diarrhoea
         subjects affected / exposed
    63 / 302 (20.86%)
    26 / 151 (17.22%)
    35 / 152 (23.03%)
         occurrences all number
    84
    36
    49
    Dry mouth
         subjects affected / exposed
    8 / 302 (2.65%)
    3 / 151 (1.99%)
    11 / 152 (7.24%)
         occurrences all number
    8
    3
    11
    Dyspepsia
         subjects affected / exposed
    32 / 302 (10.60%)
    18 / 151 (11.92%)
    6 / 152 (3.95%)
         occurrences all number
    35
    22
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    23 / 302 (7.62%)
    15 / 151 (9.93%)
    10 / 152 (6.58%)
         occurrences all number
    25
    20
    10
    Nausea
         subjects affected / exposed
    47 / 302 (15.56%)
    23 / 151 (15.23%)
    23 / 152 (15.13%)
         occurrences all number
    61
    29
    31
    Vomiting
         subjects affected / exposed
    35 / 302 (11.59%)
    13 / 151 (8.61%)
    13 / 152 (8.55%)
         occurrences all number
    42
    16
    19
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    13 / 302 (4.30%)
    6 / 151 (3.97%)
    10 / 152 (6.58%)
         occurrences all number
    13
    6
    10
    Rash
         subjects affected / exposed
    24 / 302 (7.95%)
    5 / 151 (3.31%)
    6 / 152 (3.95%)
         occurrences all number
    29
    8
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    41 / 302 (13.58%)
    23 / 151 (15.23%)
    21 / 152 (13.82%)
         occurrences all number
    58
    24
    32
    Back pain
         subjects affected / exposed
    43 / 302 (14.24%)
    23 / 151 (15.23%)
    17 / 152 (11.18%)
         occurrences all number
    52
    24
    19
    Muscle spasms
         subjects affected / exposed
    25 / 302 (8.28%)
    10 / 151 (6.62%)
    8 / 152 (5.26%)
         occurrences all number
    28
    11
    10
    Myalgia
         subjects affected / exposed
    30 / 302 (9.93%)
    18 / 151 (11.92%)
    12 / 152 (7.89%)
         occurrences all number
    35
    23
    13
    Neck pain
         subjects affected / exposed
    10 / 302 (3.31%)
    8 / 151 (5.30%)
    4 / 152 (2.63%)
         occurrences all number
    12
    12
    4
    Pain in extremity
         subjects affected / exposed
    49 / 302 (16.23%)
    22 / 151 (14.57%)
    16 / 152 (10.53%)
         occurrences all number
    61
    27
    19
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 302 (3.31%)
    8 / 151 (5.30%)
    9 / 152 (5.92%)
         occurrences all number
    11
    9
    10
    Fluid retention
         subjects affected / exposed
    16 / 302 (5.30%)
    9 / 151 (5.96%)
    7 / 152 (4.61%)
         occurrences all number
    19
    10
    7
    Hypokalaemia
         subjects affected / exposed
    17 / 302 (5.63%)
    5 / 151 (3.31%)
    8 / 152 (5.26%)
         occurrences all number
    26
    5
    8
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    34 / 302 (11.26%)
    10 / 151 (6.62%)
    7 / 152 (4.61%)
         occurrences all number
    44
    11
    13
    Influenza
         subjects affected / exposed
    14 / 302 (4.64%)
    7 / 151 (4.64%)
    9 / 152 (5.92%)
         occurrences all number
    18
    8
    10
    Nasopharyngitis
         subjects affected / exposed
    51 / 302 (16.89%)
    24 / 151 (15.89%)
    32 / 152 (21.05%)
         occurrences all number
    87
    46
    60
    Sinusitis
         subjects affected / exposed
    22 / 302 (7.28%)
    11 / 151 (7.28%)
    11 / 152 (7.24%)
         occurrences all number
    36
    15
    16
    Upper respiratory tract infection
         subjects affected / exposed
    41 / 302 (13.58%)
    22 / 151 (14.57%)
    23 / 152 (15.13%)
         occurrences all number
    60
    26
    29
    Urinary tract infection
         subjects affected / exposed
    24 / 302 (7.95%)
    18 / 151 (11.92%)
    12 / 152 (7.89%)
         occurrences all number
    25
    24
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2010
    • Clarified primary endpoint component of unsatisfactory long-term clinical response (that 2 WHO FC III symptoms to be 6 months apart rather than sustained for 6 months) • Highlighted screening and Baseline 6MWD test values must not vary by more than 10%. • Revised exclusion criteria to prohibit concomitant use of cyclosporine A. • Clarified the options for dosage following a clinical failure event • Potential Hy’s law/liver event definitions amended for consistency with other liver event definitions; clarified protocol defined serious adverse events (SAEs) and reporting timelines. • Revised Appendix 2 to align withholding of IP and nitrates with the rest of the protocol.
    17 Nov 2011
    • Primary endpoint wording clarified for hospitalization due to PAH to include both elective and non-elective hospitalizations. • Increased sample size, recruitment, and study duration, and removed the interim analyses, to increase the power of comparison. • Revised inclusion/exclusion criteria to reduce the number of subjects with multiple left heart disease risk factors. • Added “As treated” population for safety data. • Clarified to permit use of cyclosporine (ophthalmic formulation) • Allowed use of local laboratory tests at screening • Revised inclusion criteria to allow the use of right heart catheterization (RHC) in limited circumstances (applicable only in the US). • Updated testing and ordering of secondary endpoints.
    30 May 2012
    • Added modified Intent-to-Treat (mITT) population for the primary analysis based on inclusion criteria in Amendment 2, including an increase in sample size and duration to retain power for mITT analysis. • Revised exclusion criteria for previous PAH therapies and nitrate use. • Changed liver-event stopping criteria to allow stopping of ambrisentan/placebo only.
    19 Mar 2013
    • Increased sample size due to lower than anticipated (blinded) event rate. • Clarified the wording of the primary endpoint component of unsatisfactory long-term clinical response to indicate that subjects needed to only have taken one dose of randomized treatment and not been on randomized treatment for 6 months.

    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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