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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of a Single Infusion of MK-6072 (Human Monoclonal Antibody to Clostridium difficile toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium difficile toxin A and B) in Patients Receiving Antibiotic Therapy for Clostridium difficile Infection (MODIFY II)

    Summary
    EudraCT number
    2011-004994-94
    Trial protocol
    SE   ES   DE   CZ   FI   PL   GR  
    Global end of trial date
    22 May 2015

    Results information
    Results version number
    v3(current)
    This version publication date
    10 Feb 2018
    First version publication date
    12 May 2016
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    3415A-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01513239
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    MK-3415A is the combination of monoclonal antibodies to Clostridium (C.) difficile toxin A (MK- 3415) and toxin B (MK-6072). This study will investigate whether: 1) treatment with MK-6072 or MK-3415A in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium Difficile Infection (CDI) recurrence compared with placebo; and 2) MK-6072 and MK-3415A will be generally well tolerated in participants receiving SOC therapy for CDI compared with placebo.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Feb 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 17
    Country: Number of subjects enrolled
    Canada: 74
    Country: Number of subjects enrolled
    Czech Republic: 57
    Country: Number of subjects enrolled
    Finland: 20
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Japan: 95
    Country: Number of subjects enrolled
    Korea, Republic of: 66
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Spain: 94
    Country: Number of subjects enrolled
    Sweden: 56
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Turkey: 27
    Country: Number of subjects enrolled
    United States: 410
    Worldwide total number of subjects
    1203
    EEA total number of subjects
    437
    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)
    531
    From 65 to 84 years
    559
    85 years and over
    113

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Male and female participants 18 years of age or older, diagnosed with CDI and receiving SOC therapy were recruited for this trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MK-3415A + Standard Of Care (SOC)
    Arm description
    Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI
    Arm type
    Experimental

    Investigational medicinal product name
    MK-3415A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to C. difficile Toxin A and 10 mg/kg of monoclonal antibody to C. difficile Toxin B)

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole

    Arm title
    MK-6072 + Standard Of Care (SOC)
    Arm description
    Single intravenous (IV) infusion of 10 mg/kg MK-6072 + SOC for CDI
    Arm type
    Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole

    Investigational medicinal product name
    MK-6072
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile Toxin B)

    Arm title
    Placebo + Standard Of Care (SOC)
    Arm description
    Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of normal saline (0.9% sodium chloride)

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole

    Number of subjects in period 1
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Started
    397
    407
    399
    Treated
    391
    396
    381
    All Participants as Treated
    390
    396
    381
    Completed
    322
    337
    311
    Not completed
    75
    70
    88
         Death
    29
    22
    32
         Protocol deviation
    2
    2
    2
         Physician decision
    4
    4
    4
         Adverse event, non-fatal
    1
    1
    2
         Consent withdrawn by subject
    27
    29
    42
         Technical Problems
    1
    2
    -
         Lost to follow-up
    11
    10
    6
    Period 2
    Period 2 title
    Period 2: 9 Month Extension Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MK-3415A + SOC 9-ME
    Arm description
    9 Month Extension (9-ME) for participants treated with a single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC
    Arm type
    Experimental

    Investigational medicinal product name
    MK-3415A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to C. difficile Toxin A and 10 mg/kg of monoclonal antibody to C. difficile Toxin B)

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole

    Arm title
    MK-6072 + SOC 9-ME
    Arm description
    9-ME for participants treated with a single intravenous (IV) infusion of 10 mg/kg MK-6072 + SOC
    Arm type
    Experimental

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole

    Investigational medicinal product name
    MK-6072
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile Toxin B)

    Arm title
    Placebo + SOC 9-ME
    Arm description
    9-ME for participants treated with placebo: normal saline IV infusion (0.9% sodium chloride) + SOC
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of normal saline (0.9% sodium chloride)

    Investigational medicinal product name
    SOC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Standard of Care (SOC) for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole

    Number of subjects in period 2 [1]
    MK-3415A + SOC 9-ME MK-6072 + SOC 9-ME Placebo + SOC 9-ME
    Started
    112
    100
    83
    Completed
    102
    90
    78
    Not completed
    10
    10
    5
         Death
    2
    5
    2
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    5
    3
    2
         Technical Problems
    -
    1
    1
         Lost to follow-up
    2
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of participants that started the 9 month extension phase were not the same as the number completing the preceding main phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-3415A + Standard Of Care (SOC)
    Reporting group description
    Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI

    Reporting group title
    MK-6072 + Standard Of Care (SOC)
    Reporting group description
    Single intravenous (IV) infusion of 10 mg/kg MK-6072 + SOC for CDI

    Reporting group title
    Placebo + Standard Of Care (SOC)
    Reporting group description
    Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI

    Reporting group values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC) Total
    Number of subjects
    397 407 399 1203
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    150 198 183 531
        From 65-84 years
    203 177 179 559
        85 years and over
    44 32 37 113
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    65.9 ± 17.3 62.6 ± 17.5 64.3 ± 16.4 -
    Gender Categorical
    Units: Subjects
        Female
    216 220 239 675
        Male
    181 187 160 528

    End points

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    End points reporting groups
    Reporting group title
    MK-3415A + Standard Of Care (SOC)
    Reporting group description
    Single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC for CDI

    Reporting group title
    MK-6072 + Standard Of Care (SOC)
    Reporting group description
    Single intravenous (IV) infusion of 10 mg/kg MK-6072 + SOC for CDI

    Reporting group title
    Placebo + Standard Of Care (SOC)
    Reporting group description
    Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI
    Reporting group title
    MK-3415A + SOC 9-ME
    Reporting group description
    9 Month Extension (9-ME) for participants treated with a single intravenous (IV) infusion of 10 mg/kg MK-3415A + SOC

    Reporting group title
    MK-6072 + SOC 9-ME
    Reporting group description
    9-ME for participants treated with a single intravenous (IV) infusion of 10 mg/kg MK-6072 + SOC

    Reporting group title
    Placebo + SOC 9-ME
    Reporting group description
    9-ME for participants treated with placebo: normal saline IV infusion (0.9% sodium chloride) + SOC

    Primary: Percentage of participants with CDI recurrence

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    End point title
    Percentage of participants with CDI recurrence
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile after clinical cure of the initial CDI episode. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The Full Analysis Set (FAS) population is analyzed consisting of all randomized participants with participants excluded for the failure to receive infusion of study medication; for lack of a positive local stool test for toxigenic C. difficile; or for failure to receive protocol defined standard of care therapy within a 1 day window of the infusion.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    395
    378
    Units: Percentage of participants
        number (not applicable)
    14.9
    15.7
    25.7
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    -10.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.4
         upper limit
    -5.1
    Notes
    [1] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    773
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [2]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    -9.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.5
         upper limit
    -4.3
    Notes
    [2] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
    Statistical analysis title
    Comparison of MK-3415A + SOC versus MK-6072 + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v MK-6072 + Standard Of Care (SOC)
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3718 [3]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.9
         upper limit
    4.2
    Notes
    [3] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)

    Primary: Percentage of participants with one or more adverse events during 4 weeks following infusion treatment

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    End point title
    Percentage of participants with one or more adverse events during 4 weeks following infusion treatment
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. The population analyzed is all participants as treated (APaT), based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    396
    381
    Units: Percentage of participants
        number (not applicable)
    57.4
    58.1
    60.4
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    771
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.408
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.8
         upper limit
    4
    Statistical analysis title
    Comparison of 6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.517
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    4.6

    Primary: Percentage of participants with one or more drug-related adverse events during 4 weeks following infusion treatment

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    End point title
    Percentage of participants with one or more drug-related adverse events during 4 weeks following infusion treatment
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. A drug-related adverse event is determined by the investigator to be related to the drug. The population analyzed is APaT, based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    396
    381
    Units: Percentage of Participants
        number (not applicable)
    6.7
    6.8
    6.8
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    771
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.931
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    3.5
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.997
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    3.6

    Primary: Percentage of participants with one or more serious drug-related adverse events during 4 weeks following infusion treatment

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    End point title
    Percentage of participants with one or more serious drug-related adverse events during 4 weeks following infusion treatment
    End point description
    A serious adverse event (SAE) is any AE occurring at any dose or during any use of the medicinal product that results in death; or is life threatening; or results in a persistent or significant disability/incapacity; or results in or prolongs an existing inpatient hospitalization; or is a congenital anomaly/birth defect; or other important medical events. A serious drug-related adverse event is determined by the investigator to be related to the drug. The population analyzed is APaT, based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    396
    381
    Units: Percentage of participants
        number (not applicable)
    0.8
    0.0
    0.3
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    771
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.328
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    2
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.308
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.7

    Primary: Percentage of participants who discontinued study medication due to an adverse event during 4 weeks following infusion treatment

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    End point title
    Percentage of participants who discontinued study medication due to an adverse event during 4 weeks following infusion treatment
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. The population analyzed is APaT, based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    396
    381
    Units: Percentage of participants
        number (not applicable)
    0
    0
    0
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    771
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.999
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    1
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.999
    Method
    Miettinen and Nurminen
    Parameter type
    Percentage Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    1

    Primary: Percentage of participants with one or more infusion-specific adverse events on the day of infusion or the day after infusion

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    End point title
    Percentage of participants with one or more infusion-specific adverse events on the day of infusion or the day after infusion
    End point description
    An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. The population analyzed is APaT, based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 hours
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    396
    381
    Units: Percentage of participants
        number (not applicable)
    7.2
    8.8
    7.6
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    771
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Percentage Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.2
         upper limit
    3.3
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Percentage Difference
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    5.2

    Secondary: Percentage of participants with Global Cure

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    End point title
    Percentage of participants with Global Cure
    End point description
    Global cure is defined as the clinical cure of the initial CDI episode with no CDI recurrence through Week 12. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The FAS population is analyzed consisting of all randomized participants with participants excluded for the failure to receive infusion of study medication; for lack of a positive local stool test for toxigenic C. difficile; or for failure to receive protocol defined standard of care therapy within a 1 day window of the infusion.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    390
    395
    378
    Units: Percentage of participants
        number (not applicable)
    57.4
    66.8
    52.1
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0722 [4]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    12.2
    Notes
    [4] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    773
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    14.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.7
         upper limit
    21.4
    Notes
    [5] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
    Statistical analysis title
    Comparison of MK-3415A + SOC versus MK-6072 + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v MK-6072 + Standard Of Care (SOC)
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9969 [6]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    -9.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.1
         upper limit
    -2.7
    Notes
    [6] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)

    Secondary: Percentage of participants with CDI recurrence in those with clinical cure of the initial CDI episode

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    End point title
    Percentage of participants with CDI recurrence in those with clinical cure of the initial CDI episode
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The population analyzed is treated participants who achieved a clinical cure of the initial CDI episode.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    282
    326
    294
    Units: Percentage of participants
        number (not applicable)
    20.6
    19.0
    33.0
    Statistical analysis title
    Comparison of MK-3415A + SOC versus Placebo + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [7]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    -11.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19
         upper limit
    -4.7
    Notes
    [7] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
    Statistical analysis title
    Comparison of MK-6072 + SOC versus Placebo + SOC
    Comparison groups
    MK-6072 + Standard Of Care (SOC) v Placebo + Standard Of Care (SOC)
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    -13.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.4
         upper limit
    -6.9
    Notes
    [8] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
    Statistical analysis title
    Comparison of MK-3415A + SOC versus MK-6072 + SOC
    Comparison groups
    MK-3415A + Standard Of Care (SOC) v MK-6072 + Standard Of Care (SOC)
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6962 [9]
    Method
    Miettinen and Nurminen
    Parameter type
    Adjusted Difference
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.6
         upper limit
    8
    Notes
    [9] - One sided p-value based on the Miettinen and Nurminen method stratified by SOC therapy (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)

    Secondary: Percentage of participants with CDI recurrence in those with a history of CDI in the 6 months prior to enrollment

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    End point title
    Percentage of participants with CDI recurrence in those with a history of CDI in the 6 months prior to enrollment
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The population analyzed consists of treated participants with a history of CDI in the past 6 months.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    104
    113
    110
    Units: Percentage of participants
        number (not applicable)
    20.2
    23.9
    42.7
    No statistical analyses for this end point

    Secondary: Percentage of participants with CDI recurrence in those with the 027 ribotype

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    End point title
    Percentage of participants with CDI recurrence in those with the 027 ribotype
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The 027 ribotype is a more virulent, epidemic strain responsible for several outbreaks of disease associated with an increased risk of severity and mortality. The population analyzed consists of treated participants with the 027 ribotype.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    39
    43
    64
    Units: Percentage of participants
        number (not applicable)
    12.8
    20.9
    32.8
    No statistical analyses for this end point

    Secondary: Percentage of participants with CDI recurrence in those with an epidemic strain

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    End point title
    Percentage of participants with CDI recurrence in those with an epidemic strain
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. An epidemic strain includes ribotypes 027, 014, 002, 001, 106 or 020. The population analyzed consists of treated participants with an epidemic strain.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    116
    102
    127
    Units: Percentage of participants
        number (not applicable)
    14.7
    18.6
    29.1
    No statistical analyses for this end point

    Secondary: Percentage of participants with CDI recurrence in those with clinically severe CDI

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    End point title
    Percentage of participants with CDI recurrence in those with clinically severe CDI
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Participants with clinically severe CDI have a Zar Score greater than or equal to 2 points based on the presence of 1 or more of the following: 1) age >60 years old (1 point); 2) body temperature >38.3°C (>100°F) (1 point); 3) albumin level ˂2.5 mg/dl (1 point); 4) peripheral white blood cell count >15,000 cells/mm^3 within 48 hours (1 point); 5) endoscopic evidence of pseudomembranous colitis (2 points); and 6) treatment in Intensive Care Unit (2 points). The population analyzed consists of treated participants with clinically severe CDI.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    80
    55
    65
    Units: Percentage of participants
        number (not applicable)
    11.3
    10.9
    20.0
    No statistical analyses for this end point

    Secondary: Percentage of participants with CDI recurrence in those 65 years and older

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    End point title
    Percentage of participants with CDI recurrence in those 65 years and older
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The population analyzed consists of treated participants 65 years and older.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    241
    205
    206
    Units: Percentage of participants
        number (not applicable)
    17.4
    15.6
    29.6
    No statistical analyses for this end point

    Secondary: Percentage of participants with CDI recurrence in those with compromised immunity

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    End point title
    Percentage of participants with CDI recurrence in those with compromised immunity
    End point description
    CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Compromised immunity is an active hematological malignancy (including leukemia, lymphoma, multiple myeloma), an active malignancy requiring recent cytotoxic chemotherapy, receipt of a prior hematopoietic stem cell transplant, receipt of a prior solid organ transplant, asplenia, or neutropenia/pancytopenia due to other conditions. The population analyzed consists of treated participants with compromised immunity.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    MK-3415A + Standard Of Care (SOC) MK-6072 + Standard Of Care (SOC) Placebo + Standard Of Care (SOC)
    Number of subjects analysed
    85
    91
    61
    Units: Percentage of participants
        number (not applicable)
    16.5
    12.1
    26.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Main phase non-serious adverse events collected systematically up to Day 28; serious adverse events collected systematically up to Day 90. Extension phase assessed up to 9-months non-systematically.
    Adverse event reporting additional description
    Main phase AEs assessed Systematically: based on treatment actually received. One participant randomized to the MK-3415A arm was treated with MK-3415, but not with MK-6072, is placed in an arm for MK-3415. 9-Month Extension AEs were not planned for collection; and were therefore assessed Non-systematically, with a MedDRA version of 18.0.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    MK-3415A + SOC
    Reporting group description
    Single IV infusion of 10 mg/kg MK-3415A + SOC for CDI

    Reporting group title
    MK-6072 + SOC
    Reporting group description
    Single IV infusion of 10 mg/kg MK-6072 + SOC for CDI

    Reporting group title
    Placebo + SOC
    Reporting group description
    Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI

    Reporting group title
    MK-3415 + SOC
    Reporting group description
    Single intravenous (IV) infusion of 10 mg/kg MK-3415 + SOC for CDI

    Reporting group title
    MK-3415A + SOC 9-ME
    Reporting group description
    9-ME for participants treated with a single IV infusion of 10 mg/kg MK-3415A + SOC

    Reporting group title
    MK-6072 + SOC 9-ME
    Reporting group description
    9-ME for participants treated with a single IV infusion of 10 mg/kg MK-6072 + SOC

    Reporting group title
    Placebo + SOC 9-ME
    Reporting group description
    9-ME for participants treated with placebo: Normal saline IV infusion (0.9% sodium chloride) + SOC

    Serious adverse events
    MK-3415A + SOC MK-6072 + SOC Placebo + SOC MK-3415 + SOC MK-3415A + SOC 9-ME MK-6072 + SOC 9-ME Placebo + SOC 9-ME
    Total subjects affected by serious adverse events
         subjects affected / exposed
    118 / 390 (30.26%)
    111 / 396 (28.03%)
    129 / 381 (33.86%)
    1 / 1 (100.00%)
    6 / 112 (5.36%)
    7 / 100 (7.00%)
    3 / 83 (3.61%)
         number of deaths (all causes)
    31
    25
    33
    1
    2
    5
    2
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone cancer
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone cancer metastatic
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal cancer metastatic
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic leukaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medulloblastoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myeloid leukaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral T-cell lymphoma unspecified
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 390 (0.77%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Device breakage
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disuse syndrome
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suprapubic pain
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frostbite
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood lactic acid increased
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia test positive
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 390 (0.26%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    3 / 381 (0.79%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 396 (0.51%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 390 (0.26%)
    2 / 396 (0.51%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    5 / 390 (1.28%)
    3 / 396 (0.76%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 390 (0.00%)
    3 / 396 (0.76%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    5 / 390 (1.28%)
    5 / 396 (1.26%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 390 (0.77%)
    2 / 396 (0.51%)
    3 / 381 (0.79%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 390 (0.77%)
    5 / 396 (1.26%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    3 / 381 (0.79%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    2 / 100 (2.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 390 (1.03%)
    3 / 396 (0.76%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 390 (0.51%)
    3 / 396 (0.76%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 390 (0.51%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    1 / 1 (100.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Senile dementia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 390 (0.51%)
    4 / 396 (1.01%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 390 (1.03%)
    7 / 396 (1.77%)
    6 / 381 (1.57%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 7
    0 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 390 (0.26%)
    4 / 396 (1.01%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 390 (0.26%)
    2 / 396 (0.51%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    4 / 381 (1.05%)
    1 / 1 (100.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 390 (0.26%)
    2 / 396 (0.51%)
    4 / 381 (1.05%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritic syndrome
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 390 (0.26%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    1 / 100 (1.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    2 / 381 (0.52%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 396 (0.51%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock hypoglycaemic
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 390 (0.77%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective staphylococcal
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    13 / 390 (3.33%)
    14 / 396 (3.54%)
    28 / 381 (7.35%)
    0 / 1 (0.00%)
    1 / 112 (0.89%)
    0 / 100 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 15
    0 / 34
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 396 (0.25%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 396 (0.00%)
    0 / 381 (0.00%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)
    0 / 100 (0.00%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 390 (0.00%)
    0 / 396 (0.00%)
    1 / 381 (0.26%)
    0 / 1 (0.00%)
    0 / 112 (0.00%)