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    Clinical Trial Results:
    FAST- Febuxostat versus Allopurinol Streamlined Trial A prospective, randomised, open-label, blinded endpoint (PROBE) clinical trial evaluating long term cardiovascular safety of febuxostat in comparison with allopurinol in patients with chronic symptomatic hyperuricaemia

    Summary
    EudraCT number
    		 2011-001883-23
    Trial protocol
    		 GB   DK   FI   SE  
    Global end of trial date
    31 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2021
    First version publication date
    05 May 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2011CV08 (FAST)
    Additional study identifiers
    ISRCTN number
    		 ISRCTN72443728
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee
    Sponsor organisation address
    Ninewells Hospital & Medical School, Dundee, United Kingdom,
    Public contact
    Professor Tom MacDonald, MEMO Research, University of Dundee, +44 1382383119, t.m.macdonald@dundee.ac.uk
    Scientific contact
    Professor Tom MacDonald, MEMO Research, University of Dundee, +44 1382383119, t.m.macdonald@dundee.ac.uk
    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
    28 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the cardiovascular safety profile of febuxostat versus allopurinol when taken for an average of 3 years in patients over 60 years with chronic hyperuricaemia in conditions where urate deposition has already occurred
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements.
    Background therapy
    		 Treatment of acute gout flares was allowed according to clinical judgement, e.g. with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 2099
    Country: Number of subjects enrolled
    Sweden: 140
    Country: Number of subjects enrolled
    United Kingdom: 4364
    Worldwide total number of subjects
    6603
    EEA total number of subjects
    2239
    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)
    1324
    From 65 to 84 years
    5095
    85 years and over
    184

    Subject disposition

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    Recruitment
    Recruitment details
    		 Screening period from 20 December 2011 to 17 October 2017. A total of 7552 subjects were screened and 6603 consented to enroll from the UK, Denmark and Sweden. Patients were included with gout, aged over 60 years, with at least 1 additional CV risk factor and already treated with allopurinol.

    Pre-assignment
    Screening details
    		 Age was missing for 3/6603 enrolled patients (these patients are included as 65-85 in the by age summary). Of the 6603 consented patients, 6435 were eligible and either entered the lead-in phase (urate at least 6 mg/dL) or continued directly to randomization (urate below 6 mg/dL). Washout period of 1 week.

    Pre-assignment period milestones
    Number of subjects started
    		 6603
    Number of subjects completed
    		 6128

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligible: 168
    Reason: Number of subjects
    		 Withdrew prior to randomisation: 307
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The primary endpoint was blinded. Cardiovascular events were adjudicated by an independent committee that was blinded to randomisation and subsequent treatment groups. Recruitment and blinded accumulation of study endpoints were reviewed by the study steering committee on an ongoing basis. The pharmacovigilance group reviewed blinded SAEs.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Febuxostat
    Arm description
    		 All patients randomised to febuxostat treatment received 80 mg initially and sUA level was determined after 2 weeks of treatment (range 9 to 24 days). Patients with a sUA level of ≥6 mg/dL had their dose increased to febuxostat 120 mg daily, followed by the determination of their sUA level 2 weeks later. Patients then continued to receive treatment according to clinical judgement, EULAR recommendations and the current SmPC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Febuxostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients randomised to febuxostat treatment received 80 mg initially and sUA level was determined after 2 weeks of treatment (range 9 to 24 days). Patients with a sUA level of ≥6 mg/dL had their dose increased to febuxostat 120 mg daily, followed by the determination of their sUA level 2 weeks later. Patients then continued to receive treatment according to clinical judgement, EULAR recommendations and the current SmPC.

    Arm title
    		 Allopurinol
    Arm description
    		 In accordance with the current SmPC, allopurinol dosing could be in the range of 100 to 900 mg per day. Patients randomised to allopurinol received allopurinol at the dose determined before randomisation. During the course of the study, the dose was adjusted according to clinical judgement as determined by EULAR recommendations and the current SmPC.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    allopurinol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In accordance with the current SmPC, allopurinol dosing could be in the range of 100 to 900 mg per day. Patients randomised to allopurinol received allopurinol at the dose determined before randomisation. During the course of the study, the dose was adjusted according to clinical judgement as determined by EULAR recommendations and the current SmPC.

    Number of subjects in period 1 [1]
    		Febuxostat Allopurinol
    Started
    3063
    3065
    Completed
    2652
    2633
    Not completed
    411
    432
         Physician decision
    20
    17
         Consent withdrawn by subject
    107
    98
         died
    222
    263
         moved from study area
    15
    26
         Adverse event
    28
    11
         other
    -
    1
         Serious adverse event
    12
    9
         Lost to follow-up
    2
    1
         Protocol deviation
    5
    6
    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: Only 6128 randomized patients are included in the "overall trial" and therefore the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Febuxostat
    Reporting group description
    		 All patients randomised to febuxostat treatment received 80 mg initially and sUA level was determined after 2 weeks of treatment (range 9 to 24 days). Patients with a sUA level of ≥6 mg/dL had their dose increased to febuxostat 120 mg daily, followed by the determination of their sUA level 2 weeks later. Patients then continued to receive treatment according to clinical judgement, EULAR recommendations and the current SmPC.

    Reporting group title
    Allopurinol
    Reporting group description
    		 In accordance with the current SmPC, allopurinol dosing could be in the range of 100 to 900 mg per day. Patients randomised to allopurinol received allopurinol at the dose determined before randomisation. During the course of the study, the dose was adjusted according to clinical judgement as determined by EULAR recommendations and the current SmPC.

    Reporting group values
    		 Febuxostat Allopurinol Total
    Number of subjects
    		 3063 3065 6128
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.99 ( 6.37 ) 70.90 ( 6.50 ) -
    Gender categorical
    Units: Subjects
        Female
    		 444 459 903
        Male
    		 2619 2606 5225
    Race
    Units: Subjects
        White
    		 3034 3036 6070
        Asian
    		 11 14 25
        Afro-Carribbean
    		 10 8 18
        Oriental
    		 2 1 3
        Other
    		 6 6 12
    Allopurinol dose up-titrated during lead-in
    Units: Subjects
        Yes
    		 1104 1097 2201
        No
    		 1959 1968 3927
    Duration of allopurinol treatment
    At time of screening
    Units: years
        arithmetic mean (standard deviation)
    		 9.35 ( 9.28 ) 9.48 ( 9.31 ) -

    End points

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    End points reporting groups
    Reporting group title
    Febuxostat
    Reporting group description
    		 All patients randomised to febuxostat treatment received 80 mg initially and sUA level was determined after 2 weeks of treatment (range 9 to 24 days). Patients with a sUA level of ≥6 mg/dL had their dose increased to febuxostat 120 mg daily, followed by the determination of their sUA level 2 weeks later. Patients then continued to receive treatment according to clinical judgement, EULAR recommendations and the current SmPC.

    Reporting group title
    Allopurinol
    Reporting group description
    		 In accordance with the current SmPC, allopurinol dosing could be in the range of 100 to 900 mg per day. Patients randomised to allopurinol received allopurinol at the dose determined before randomisation. During the course of the study, the dose was adjusted according to clinical judgement as determined by EULAR recommendations and the current SmPC.

    Primary: Primary outcome (on-treatment)

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    End point title
    		 Primary outcome (on-treatment)
    End point description
    The Anti-Platelet Trialists’ Collaboration primary composite endpoint included hospitalisation for non-fatal MI/biomarker positive ACS, non-fatal stroke [whether reported to have been hospitalised, non-hospitalised or to have occurred during a hospitalisation] or death due to a CV event.
    End point type
    Primary
    End point timeframe
    Time from randomization to first occurrence of a primary endpoint event.
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Primary endpoint
    172
    241
    Attachments
    		 Primary on-treatment analysis
    Statistical analysis title
    		 On-treatment analysis
    Statistical analysis description
    The OT analysis censored patients after permanent discontinuation from original randomised therapy, death from any cause not included in the endpoint being considered, date of withdrawal of all consent to participate further in the study, date of loss to follow-up or end of study, whichever occurred first.
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.03
    Notes
    [1] - Non-inferiority was to be claimed if the upper limit of the 95% CI for the HR was ≤1.3.
    [2] - The hazard ratio (febuxostat versus allopurinol) in a Cox proportional hazards model was assessed for non-inferiority (limit of 1·3). All analyses were adjusted for the stratification variable and country. P-value was calculated from Wald statistic

    Primary: Primary outcome (intent-to-treat)

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    End point title
    		 Primary outcome (intent-to-treat)
    End point description
    The Anti-Platelet Trialist' Collaboration primary composite endpoint included hospitalisation for non-fatal MI/biomarker positive ACS, non-fatal stroke [whether reported to have been hospitalised, non-hospitalised or to have occurred during a hospitalisation] or death due to a CV event.
    End point type
    Primary
    End point timeframe
    Time from randomization to first occurrence of a primary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Primary event
    256
    285
    Attachments
    		 Untitled (Filename: FAST_FIGURE2a_PRIM_OT.pdf)
    Statistical analysis title
    		 Intent-to-treat analysis
    Statistical analysis description
    The ITT analysis censored patients after death from any cause not included in the endpoint being considered, date of withdrawal of all consent to participate further in the study, date of loss to follow-up or end of study, whichever occurred first.
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.185 [4]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.06
    Notes
    [3] - If non-inferiority was demonstrated, a superiority analysis was carried out based on ITT.
    [4] - The type I error rate was set at 5% for 2-sided superiority analyses. P-value was calculated from Wald statistics. Superiority of febuxostat for the primary outcome was not demonstrated.
    Statistical analysis title
    		 Intent-to-treat analysis
    Statistical analysis description
    The ITT analysis censored patients after death from any cause not included in the endpoint being considered, date of withdrawal of all consent to participate further in the study, date of loss to follow-up or end of study, whichever occurred first.
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.06
    Notes
    [5] - The first analysis to be carried out was a non-inferiority analysis of the primary outcome based on an OT analysis (covering the period patients remain on randomized therapy), with a supporting non-inferiority analysis using an ITT analysis.
    [6] - The ITT analysis of the primary endpoint confirmed non-inferiority of febuxostat

    Secondary: Secondary - hospitalisation for non-fatal MI/ACS (on-treatment)

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    End point title
    		 Secondary - hospitalisation for non-fatal MI/ACS (on-treatment)
    End point description
    Secondary endpoint event of hospitalisation for non-fatal myocardial infarction/ biomarker positive acute coronary syndrome
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Hospitilsation for non-fatal MI/ACS
    77
    98
    Statistical analysis title
    		 On-treatment analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.016
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.27

    Secondary: Secondary - non-fatal stroke (on-treatment)

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    End point title
    		 Secondary - non-fatal stroke (on-treatment)
    End point description
    Secondary endpoint of non-fatal stroke
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    58
    80
    Statistical analysis title
    		 On-treatment analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.21

    Secondary: Secondary - cardiovascular death (on-treatment)

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    End point title
    		 Secondary - cardiovascular death (on-treatment)
    End point description
    Secondary endpoint of cardiovascular death.
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    62
    82
    Attachments
    		 Untitled (Filename: FAST_FIGURE3c_CVDEATH_OT.pdf)
    Statistical analysis title
    		 On-treatment analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.018
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.27

    Secondary: Secondary - all-cause mortality (on-treatment)

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    End point title
    		 Secondary - all-cause mortality (on-treatment)
    End point description
    Secondary endpoint of all-cause mortality
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    108
    174
    Attachments
    		 Untitled (Filename: FAST_FIGURE3a_ACM_OT.pdf)
    Statistical analysis title
    		 On-treatment analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.95

    Secondary: Secondary - hospitalisation for non-fatal MI/ACS (intent-to-treat)

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    End point title
    		 Secondary - hospitalisation for non-fatal MI/ACS (intent-to-treat)
    End point description
    Secondary endpoint of hospitalisation for non-fatal myocardial infarction/biomarker positive acute coronary syndrome
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    102
    110
    Statistical analysis title
    		 Intent-to-treat analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.007
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.21

    Secondary: Secondary - non-fatal stroke (intent-to-treat)

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    End point title
    		 Secondary - non-fatal stroke (intent-to-treat)
    End point description
    Secondary endpoint of non-fatal stroke
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    80
    87
    Statistical analysis title
    		 Intent-to-treat analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.013
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.25

    Secondary: Secondary - cardiovascular death (intent-to-treat)

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    End point title
    		 Secondary - cardiovascular death (intent-to-treat)
    End point description
    Secondary endpoint of cardiovascular death
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    117
    122
    Attachments
    		 Untitled (Filename: FAST_FIGURE3d_CVDEATH_ITT.pdf)
    Statistical analysis title
    		 Intent-to-treat analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.23

    Secondary: Secondary - all-cause mortality (intent-to-treat)

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    End point title
    		 Secondary - all-cause mortality (intent-to-treat)
    End point description
    Secondary endpoint of all-cause mortality
    End point type
    Secondary
    End point timeframe
    Time from randomization to first occurrence of the secondary endpoint event
    End point values
    		 Febuxostat Allopurinol
    Number of subjects analysed
    3063
    3065
    Units: subjects
        Secondary event
    222
    263
    Attachments
    		 Untitled (Filename: FAST_FIGURE3b_ACM_ITT.pdf)
    Statistical analysis title
    		 Intent-to-treat analysis
    Comparison groups
    Febuxostat v Allopurinol
    Number of subjects included in analysis
    6128
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.01

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Summaries of AEs are presented for during treatment (randomisation up to date of death or end of study IMP plus 28 days, whichever came first).
    Adverse event reporting additional description
    SAEs (related or unrelated to study treatment) and AEs only considered related to treatment were recorded during the stud and collected separately. Related SAE data do not overlap with related AE data. "Occurrence" equals number of patients. Total of non-serious AEs equals summation of each AE term with incidence >1% and is not an overall total.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Febuxostat (safety population) - during the treatment period
    Reporting group description
    		 The safety population was defined as the randomized population, excluding those patients where there was clear evidence that no study drug was taken. During treatment is defined as randomization up to date of death or end of study IMP plus 28 days, whichever came first.

    Reporting group title
    Allopurinol (safety population) - during the treatment period
    Reporting group description
    		 The safety population was defined as the randomised population, excluding those patients where there was clear evidence that no study drug was taken. During treatment is defined as randomisation up to date of death or end of study IMP plus 28 days, whichever came first.

    Serious adverse events
    		 Febuxostat (safety population) - during the treatment period Allopurinol (safety population) - during the treatment period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1527 / 3001 (50.88%)
    1771 / 3050 (58.07%)
         number of deaths (all causes)
    147
    224
         number of deaths resulting from adverse events
    147
    224
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin cancer
         subjects affected / exposed
    53 / 3001 (1.77%)
    70 / 3050 (2.30%)
         occurrences causally related to treatment / all
    0 / 53
    0 / 70
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    47 / 3001 (1.57%)
    65 / 3050 (2.13%)
         occurrences causally related to treatment / all
    0 / 47
    0 / 65
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    15 / 3001 (0.50%)
    19 / 3050 (0.62%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 19
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Pancreatic carcinoma
         subjects affected / exposed
    9 / 3001 (0.30%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Lung cancer metastatic
         subjects affected / exposed
    5 / 3001 (0.17%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Brain neoplasm
         subjects affected / exposed
    1 / 3001 (0.03%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Neoplasm malignant
         subjects affected / exposed
    5 / 3001 (0.17%)
    7 / 3050 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Hepatic neoplasm malignant
         subjects affected / exposed
    8 / 3001 (0.27%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Bladder cancer
         subjects affected / exposed
    11 / 3001 (0.37%)
    14 / 3050 (0.46%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 14
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Colon cancer
         subjects affected / exposed
    12 / 3001 (0.40%)
    19 / 3050 (0.62%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 19
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Prostate cancer metastatic
         subjects affected / exposed
    3 / 3001 (0.10%)
    7 / 3050 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Bile duct cancer
         subjects affected / exposed
    2 / 3001 (0.07%)
    6 / 3050 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Colon cancer metastatic
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Colorectal cancer
         subjects affected / exposed
    3 / 3001 (0.10%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 3001 (0.07%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    2 / 3001 (0.07%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    3 / 3001 (0.10%)
    16 / 3050 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Metastases to central nervous system
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oesophageal carcinoma
         subjects affected / exposed
    5 / 3001 (0.17%)
    6 / 3050 (0.20%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal cancer
         subjects affected / exposed
    6 / 3001 (0.20%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bone sarcoma
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 3001 (0.00%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric cancer
         subjects affected / exposed
    2 / 3001 (0.07%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemia plasmacytic
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lymphoma
         subjects affected / exposed
    2 / 3001 (0.07%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant neoplasm of renal pelvis
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mantle cell lymphoma
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mesothelioma
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to abdominal cavity
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lung
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic gastric cancer
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    5 / 3001 (0.17%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-small cell lung cancer stage IV
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian cancer
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal cancer
         subjects affected / exposed
    10 / 3001 (0.33%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sarcoma
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small intestine carcinoma metastatic
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ureteric cancer metastatic
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Uterine cancer
         subjects affected / exposed
    2 / 3001 (0.07%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    3 / 3001 (0.10%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Aortic aneurysm
         subjects affected / exposed
    10 / 3001 (0.33%)
    11 / 3050 (0.36%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Aortic stenosis
         subjects affected / exposed
    11 / 3001 (0.37%)
    13 / 3050 (0.43%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Circulatory collapse
         subjects affected / exposed
    20 / 3001 (0.67%)
    27 / 3050 (0.89%)
         occurrences causally related to treatment / all
    1 / 20
    0 / 27
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    11 / 3001 (0.37%)
    20 / 3050 (0.66%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 20
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Aneurysm ruptured
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteriosclerosis
         subjects affected / exposed
    12 / 3001 (0.40%)
    26 / 3050 (0.85%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vasculitis
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    23 / 3001 (0.77%)
    41 / 3050 (1.34%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 41
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    25 / 3001 (0.83%)
    34 / 3050 (1.11%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endarterectomy
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pacemaker generated rhythm
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Palliative care
         subjects affected / exposed
    2 / 3001 (0.07%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Proctocolectomy
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    52 / 3001 (1.73%)
    87 / 3050 (2.85%)
         occurrences causally related to treatment / all
    0 / 52
    0 / 87
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    14 / 3001 (0.47%)
    19 / 3050 (0.62%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 19
         deaths causally related to treatment / all
    0 / 14
    0 / 19
    Sudden cardiac death
         subjects affected / exposed
    6 / 3001 (0.20%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 6
    0 / 1
    Sudden death
         subjects affected / exposed
    2 / 3001 (0.07%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    General physical health deterioration
         subjects affected / exposed
    3 / 3001 (0.10%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac death
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multi-organ failure
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 3001 (0.17%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Social circumstances
    Elderly
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    37 / 3001 (1.23%)
    33 / 3050 (1.08%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 33
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Respiratory failure
         subjects affected / exposed
    7 / 3001 (0.23%)
    9 / 3050 (0.30%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Pulmonary embolism
         subjects affected / exposed
    25 / 3001 (0.83%)
    31 / 3050 (1.02%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 31
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    2 / 3001 (0.07%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pneumonia aspiration
         subjects affected / exposed
    2 / 3001 (0.07%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    2 / 3001 (0.07%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    27 / 3001 (0.90%)
    29 / 3050 (0.95%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 29
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    6 / 3001 (0.20%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Laryngeal oedema
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 3001 (0.07%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory arrest
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    9 / 3001 (0.30%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Delirium
         subjects affected / exposed
    6 / 3001 (0.20%)
    9 / 3050 (0.30%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Korsakoff's psychosis alcoholic
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Heart rate irregular
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    19 / 3001 (0.63%)
    32 / 3050 (1.05%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 32
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    9 / 3001 (0.30%)
    9 / 3050 (0.30%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Alcohol poisoning
         subjects affected / exposed
    2 / 3001 (0.07%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Head injury
         subjects affected / exposed
    10 / 3001 (0.33%)
    13 / 3050 (0.43%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multiple injuries
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Post procedural complication
         subjects affected / exposed
    3 / 3001 (0.10%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Road traffic accident
         subjects affected / exposed
    2 / 3001 (0.07%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal cord injury
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    4 / 3001 (0.13%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    131 / 3001 (4.37%)
    145 / 3050 (4.75%)
         occurrences causally related to treatment / all
    3 / 131
    0 / 145
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    41 / 3001 (1.37%)
    52 / 3050 (1.70%)
         occurrences causally related to treatment / all
    0 / 41
    0 / 52
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    Myocardial infarction
         subjects affected / exposed
    40 / 3001 (1.33%)
    45 / 3050 (1.48%)
         occurrences causally related to treatment / all
    0 / 40
    0 / 40
         deaths causally related to treatment / all
    0 / 4
    0 / 10
    Acute myocardial infarction
         subjects affected / exposed
    22 / 3001 (0.73%)
    50 / 3050 (1.64%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 50
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Angina pectoris
         subjects affected / exposed
    35 / 3001 (1.17%)
    28 / 3050 (0.92%)
         occurrences causally related to treatment / all
    0 / 35
    2 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    22 / 3001 (0.73%)
    23 / 3050 (0.75%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 23
         deaths causally related to treatment / all
    0 / 16
    0 / 16
    Cardiac disorder
         subjects affected / exposed
    4 / 3001 (0.13%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Myocardial ischaemia
         subjects affected / exposed
    6 / 3001 (0.20%)
    14 / 3050 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 14
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Cardiac failure congestive
         subjects affected / exposed
    17 / 3001 (0.57%)
    17 / 3050 (0.56%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Left ventricular dysfunction
         subjects affected / exposed
    8 / 3001 (0.27%)
    12 / 3050 (0.39%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    3 / 3001 (0.10%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    3 / 3001 (0.10%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    2 / 3001 (0.07%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    10 / 3001 (0.33%)
    12 / 3050 (0.39%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Heart valve incompetence
         subjects affected / exposed
    3 / 3001 (0.10%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Right ventricular failure
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    2 / 3001 (0.07%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    7 / 3001 (0.23%)
    5 / 3050 (0.16%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    38 / 3001 (1.27%)
    44 / 3050 (1.44%)
         occurrences causally related to treatment / all
    0 / 38
    0 / 44
         deaths causally related to treatment / all
    0 / 7
    0 / 4
    Transient ischaemic attack
         subjects affected / exposed
    33 / 3001 (1.10%)
    47 / 3050 (1.54%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 47
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    8 / 3001 (0.27%)
    16 / 3050 (0.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 16
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 3001 (0.03%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cerebral haematoma
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coma hepatic
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    2 / 3001 (0.07%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 3001 (0.07%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Motor neurone disease
         subjects affected / exposed
    2 / 3001 (0.07%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal cord depression
         subjects affected / exposed
    3 / 3001 (0.10%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    3 / 3001 (0.10%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia haemolytic autoimmune
         subjects affected / exposed
    2 / 3001 (0.07%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    121 / 3001 (4.03%)
    140 / 3050 (4.59%)
         occurrences causally related to treatment / all
    0 / 121
    0 / 140
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    7 / 3001 (0.23%)
    14 / 3050 (0.46%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 14
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 3001 (0.03%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pancreatitis
         subjects affected / exposed
    12 / 3001 (0.40%)
    9 / 3050 (0.30%)
         occurrences causally related to treatment / all
    2 / 12
    0 / 9
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Abdominal pain
         subjects affected / exposed
    11 / 3001 (0.37%)
    30 / 3050 (0.98%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis ischaemic
         subjects affected / exposed
    3 / 3001 (0.10%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diarrhoea
         subjects affected / exposed
    14 / 3001 (0.47%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    3 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gallstone ileus
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastritis erosive
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    3 / 3001 (0.10%)
    6 / 3050 (0.20%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    8 / 3001 (0.27%)
    11 / 3050 (0.36%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 3001 (0.10%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    6 / 3001 (0.20%)
    7 / 3050 (0.23%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatic cirrhosis
         subjects affected / exposed
    7 / 3001 (0.23%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Alcoholic liver disease
         subjects affected / exposed
    1 / 3001 (0.03%)
    4 / 3050 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholecystitis
         subjects affected / exposed
    10 / 3001 (0.33%)
    18 / 3050 (0.59%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 18
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    4 / 3001 (0.13%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    43 / 3001 (1.43%)
    22 / 3050 (0.72%)
         occurrences causally related to treatment / all
    1 / 43
    0 / 22
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Renal failure
         subjects affected / exposed
    6 / 3001 (0.20%)
    13 / 3050 (0.43%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 13
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Renal failure chronic
         subjects affected / exposed
    8 / 3001 (0.27%)
    7 / 3050 (0.23%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Renal impairment
         subjects affected / exposed
    5 / 3001 (0.17%)
    10 / 3050 (0.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Proteinuria
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal disorder
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    101 / 3001 (3.37%)
    109 / 3050 (3.57%)
         occurrences causally related to treatment / all
    0 / 101
    0 / 109
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 3001 (0.00%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rheumatoid arthritis
         subjects affected / exposed
    4 / 3001 (0.13%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    92 / 3001 (3.07%)
    127 / 3050 (4.16%)
         occurrences causally related to treatment / all
    0 / 92
    0 / 127
         deaths causally related to treatment / all
    0 / 9
    0 / 14
    Lower respiratory tract infection
         subjects affected / exposed
    29 / 3001 (0.97%)
    43 / 3050 (1.41%)
         occurrences causally related to treatment / all
    0 / 29
    0 / 43
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Urinary tract infection
         subjects affected / exposed
    29 / 3001 (0.97%)
    38 / 3050 (1.25%)
         occurrences causally related to treatment / all
    0 / 29
    0 / 38
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Sepsis
         subjects affected / exposed
    19 / 3001 (0.63%)
    38 / 3050 (1.25%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 38
         deaths causally related to treatment / all
    0 / 4
    0 / 11
    Urosepsis
         subjects affected / exposed
    16 / 3001 (0.53%)
    14 / 3050 (0.46%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 14
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Bronchopneumonia
         subjects affected / exposed
    2 / 3001 (0.07%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Neutropenic sepsis
         subjects affected / exposed
    1 / 3001 (0.03%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 3001 (0.00%)
    2 / 3050 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Bacterial infection
         subjects affected / exposed
    2 / 3001 (0.07%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    21 / 3001 (0.70%)
    22 / 3050 (0.72%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Creutzfeldt-Jakob disease
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Endocarditis
         subjects affected / exposed
    3 / 3001 (0.10%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Erysipelas
         subjects affected / exposed
    15 / 3001 (0.50%)
    14 / 3050 (0.46%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    8 / 3001 (0.27%)
    9 / 3050 (0.30%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peritonitis bacterial
         subjects affected / exposed
    1 / 3001 (0.03%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post procedural infection
         subjects affected / exposed
    8 / 3001 (0.27%)
    8 / 3050 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    3 / 3001 (0.10%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    5 / 3001 (0.17%)
    6 / 3050 (0.20%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 3001 (0.00%)
    3 / 3050 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    45 / 3001 (1.50%)
    64 / 3050 (2.10%)
         occurrences causally related to treatment / all
    0 / 45
    0 / 64
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    9 / 3001 (0.30%)
    9 / 3050 (0.30%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Calcium metabolism disorder
         subjects affected / exposed
    0 / 3001 (0.00%)
    1 / 3050 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetes mellitus
         subjects affected / exposed
    9 / 3001 (0.30%)
    13 / 3050 (0.43%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 3001 (0.03%)
    0 / 3050 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Febuxostat (safety population) - during the treatment period Allopurinol (safety population) - during the treatment period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    686 / 3001 (22.86%)
    132 / 3050 (4.33%)
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    48 / 3001 (1.60%)
    5 / 3050 (0.16%)
         occurrences all number
    48
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    62 / 3001 (2.07%)
    9 / 3050 (0.30%)
         occurrences all number
    62
    9
    Dizziness
         subjects affected / exposed
    41 / 3001 (1.37%)
    14 / 3050 (0.46%)
         occurrences all number
    41
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    48 / 3001 (1.60%)
    3 / 3050 (0.10%)
         occurrences all number
    48
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    154 / 3001 (5.13%)
    18 / 3050 (0.59%)
         occurrences all number
    154
    18
    Nausea
         subjects affected / exposed
    55 / 3001 (1.83%)
    5 / 3050 (0.16%)
         occurrences all number
    55
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    31 / 3001 (1.03%)
    4 / 3050 (0.13%)
         occurrences all number
    31
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    60 / 3001 (2.00%)
    20 / 3050 (0.66%)
         occurrences all number
    60
    20
    Pruritus
         subjects affected / exposed
    32 / 3001 (1.07%)
    12 / 3050 (0.39%)
         occurrences all number
    32
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    46 / 3001 (1.53%)
    9 / 3050 (0.30%)
         occurrences all number
    46
    9
    Pain in extremity
         subjects affected / exposed
    39 / 3001 (1.30%)
    9 / 3050 (0.30%)
         occurrences all number
    39
    9
    Myalgia
         subjects affected / exposed
    32 / 3001 (1.07%)
    4 / 3050 (0.13%)
         occurrences all number
    32
    4
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    38 / 3001 (1.27%)
    20 / 3050 (0.66%)
         occurrences all number
    38
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The study was slightly underpowered at approximately 77% power to exclude a non-inferiority limit of 1.3 or alternatively alternatively, 80% power to exclude a non-inferiority limit of 1.315. The impact is considered modest.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33181081
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