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    Clinical Trial Results:
    International Randomized Double Blind Study Evaluating the Efficacy and the Safety of Clopidogrel 0.2 mg/kg Once Daily Versus Placebo in Neonates and Infants With Cyanotic Congenital Heart Disease Palliated With Systemic to Pulmonary Artery Shunt

    Summary
    EudraCT number
    		 2006-000946-38
    Trial protocol
    		 BE   GB   DE   FI   SE   DK   PT   FR   HU   IT   NL   Outside EU/EEA  
    Global end of trial date
    01 Feb 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2016
    First version publication date
    16 May 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC5314
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00396877
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & developpement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin , France, 91380
    Public contact
    Trial transparency team, Sanofi aventis recherche & developpement, Contact-US@sanofi.com
    Scientific contact
    Trial transparency team, Sanofi aventis recherche & developpement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000049-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Feb 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Clopidogrel 0.2 mg/kg/day for the reduction of all cause mortality and shunt related morbidity in neonates or infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt (e.g. modified Blalock Taussig Shunt [BTS]).
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 52
    Country: Number of subjects enrolled
    Brazil: 65
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Norway: 16
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Mexico: 69
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    South Africa: 26
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Egypt: 10
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 113
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 21
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    India: 47
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    United States: 178
    Worldwide total number of subjects
    906
    EEA total number of subjects
    346
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    404
    Infants and toddlers (28 days-23 months)
    502
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was initially planned with a minimum of 490 subjects anticipating that it would continue until a total of 172 subjects reaching primary endpoint criteria is achieved. Finally 906 subjects were enrolled and randomized between November 2006 and October 2009 in 134 sites in 31 countries. Actual median follow-up was 5.8 months.

    Pre-assignment
    Screening details
    		 A subject was considered randomized when informed consent had been obtained and there was confirmation of successful allocation of a randomization number through the study treatment allocation system (Interactive Voice Response System).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Eligible subjects were randomized to receive either Clopidogrel or placebo in a 1:1 ration without the disclosure of assigned treatments to the investigator and to the subject's parents/guardians. Both the Clopidogrel and placebo were reconstituted in the same fashion and were similar in appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Clopidogrel matching placebo until primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or common study-end-date, whichever came first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Gastroenteral use, Oral use
    Dosage and administration details
    Placebo to be administered once daily with a graduated syringe in the mouth or via a feeding tube.

    Arm title
    		 Clopidogrel 0.2 mg/kg/Day
    Arm description
    		 Clopidogrel until the primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or the common study-end-date, whichever came first
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    SR25990
    Other name
    Plavix
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Gastroenteral use, Oral use
    Dosage and administration details
    Clopidogrel administered once daily with a graduated syringe in the mouth or via a feeding tube. Dose: daily dose adjusted for weight.

    Number of subjects in period 1
    		Placebo Clopidogrel 0.2 mg/kg/Day
    Started
    439
    467
    Treated
    436
    464
    Completed
    433
    459
    Not completed
    6
    8
         Lost to follow-up
    2
    1
         Parent(s)/guardian(s)'s request
    4
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Clopidogrel matching placebo until primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or common study-end-date, whichever came first.

    Reporting group title
    Clopidogrel 0.2 mg/kg/Day
    Reporting group description
    		 Clopidogrel until the primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or the common study-end-date, whichever came first

    Reporting group values
    		 Placebo Clopidogrel 0.2 mg/kg/Day Total
    Number of subjects
    		 439 467 906
    Age categorical
    Units: Subjects
        ≤ 30 days
    		 223 238 461
        30 (<) - 92 days
    		 216 229 445
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 36 ( 22.5 ) 36.1 ( 22.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 185 198 383
        Male
    		 254 269 523
    Region of Enrollment
    Units: Subjects
        United States
    		 90 88 178
        Portugal
    		 10 10 20
        Taiwan
    		 12 10 22
        Hong Kong
    		 1 0 1
        Thailand
    		 2 3 5
        Spain
    		 16 14 30
        Israel
    		 3 4 7
        Russian Federation
    		 13 15 28
        Italy
    		 20 19 39
        India
    		 20 27 47
        France
    		 11 10 21
        Malaysia
    		 5 4 9
        Denmark
    		 3 3 6
        South Africa
    		 13 13 26
        Netherlands
    		 2 4 6
        China
    		 10 11 21
        Korea, Republic of
    		 3 2 5
        Finland
    		 2 1 3
        United Kingdom
    		 16 16 32
        Egypt
    		 4 6 10
        Hungary
    		 9 9 18
        Mexico
    		 32 37 69
        Canada
    		 5 6 11
        Argentina
    		 24 28 52
        Brazil
    		 31 34 65
        Belgium
    		 9 12 21
        Poland
    		 3 7 10
        Singapore
    		 2 2 4
        Germany
    		 54 59 113
        Norway
    		 8 8 16
        Sweden
    		 6 5 11
    Type of systemic-to-pulmonary artery shunt palliation
    One subject didn't have a systemic-to-pulmonary artery shunt but underwent stenting of the right ventricular outflow track.
    Units: Subjects
        Modified Blalock Taussig Shunt With Norwood
    		 51 62 113
        Modified Blalock Taussig Shunt Without Norwood
    		 252 257 509
        Sano Procedure With Norwood
    		 54 60 114
        Sano Procedure Without Norwood
    		 2 5 7
        Central Shunt
    		 38 40 78
        Stent of Ductus Arteriosus
    		 42 42 84
        Not Applicable
    		 0 1 1
    Shunt on cardiopulmonary bypass
    Units: Subjects
        Yes
    		 177 194 371
        No
    		 262 273 535
    Time from shunt palliation to randomization
    Units: Subjects
        less than or equal to (<=) 1 week
    		 116 113 229
        1 (less than [<]) to 2 weeks
    		 105 126 231
        2 (<) to 4 weeks
    		 117 119 236
        greater than (>) 4 weeks
    		 101 109 210
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 3.5 ( 0.7 ) 3.4 ( 0.7 ) -
    Age at shunt palliation
    Units: Days
        arithmetic mean (standard deviation)
    		 16 ( 18.7 ) 16.2 ( 18.6 ) -
    Height
    Units: Centimeters (cm)
        arithmetic mean (standard deviation)
    		 51.8 ( 4.6 ) 51.4 ( 4.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Clopidogrel matching placebo until primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or common study-end-date, whichever came first.

    Reporting group title
    Clopidogrel 0.2 mg/kg/Day
    Reporting group description
    		 Clopidogrel until the primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or the common study-end-date, whichever came first

    Primary: Number of Subjects Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature)

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    End point title
    		 Number of Subjects Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature)
    End point description
    The primary endpoint was the first occurrence of any of the following events: Death (including heart transplant); Shunt thrombosis requiring intervention; Hospitalization for bi-directional Glenn procedure or any cardiac related intervention prior to 120 days of age following an event or a shunt narrowing considered being of thrombotic nature by the blinded adjudication committee. Only the first event was counted. The analysis was performed on the intent-to-treat (ITT) population (i.e. all randomized subjects irrespective of whether or not the subject actually received study drug or the subject's compliance with the study protocol). Subjects were included in the treatment group to which they were originally allocated.
    End point type
    Primary
    End point timeframe
    Median follow-up of 5.8 months (up to a maximum of 12 months after randomization)
    End point values
    		 Placebo Clopidogrel 0.2 mg/kg/Day
    Number of subjects analysed
    439
    467
    Units: Subjects
        Death / Shunt Thrombosis / Cardiac Procedure
    90
    89
        - Death
    60
    51
        - Shunt thrombosis
    21
    26
        - Cardiac procedure <120 days of thrombotic nature
    9
    12
    Statistical analysis title
    		 Clopidogrel 0.2 mg/kg/Day vs. Placebo
    Statistical analysis description
    Due to the limited knowledge in this population, 3 interim analyses were performed at approximately 40%, 60%, 80% and 100% of maximum number of 172 required primary efficacy events to evaluate the effect of Clopidogrel on endpoint with potential to end trial in case of a clear efficacy advantage for Clopidogrel. Study was designed with 80% power and an overall type I error rate of 5%. Relative Risk Reduction (Clopidogrel vs placebo) and 95% CI estimated using Cox's proportional hazards model
    Comparison groups
    Placebo v Clopidogrel 0.2 mg/kg/Day
    Number of subjects included in analysis
    906
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.434 [1]
    Method
    		 Logrank
    Parameter type
    		 Relative Risk Reduction (%)
    Point estimate
    11.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.2
         upper limit
    		 33.6
    Notes
    [1] - The a-priori threshold for statistical significance was < 0.035 reflecting the adjustment for interim analyses. No other adjustment for multiplicity was made.

    Secondary: Number of Subjects With Bleeding Events

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    End point title
    		 Number of Subjects With Bleeding Events
    End point description
    Bleeding events spanning from signature of the Informed Consent Form up to the last visit were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from randomization up until 28 days after treatment discontinuation or final follow-up visit, whichever came first, and subjects who experienced bleeding events during that period were counted. The analysis was performed on the exposed population (i.e. all randomized subjects who received at least one dose of study drug regardless of the amount of treatment received). Subjects were included in the treatment group according to the treatment received.
    End point type
    Secondary
    End point timeframe
    From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first
    End point values
    		 Placebo Clopidogrel 0.2 mg/kg/Day
    Number of subjects analysed
    436
    464
    Units: Subjects
        Any bleeding event
    88
    87
        - Serious
    32
    30
        - Serious with an outcome of death
    1
    1
        - Leading to permanent treatment discontinuation
    9
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects According to Bleeding Type/Etiology

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    End point title
    		 Number of Subjects According to Bleeding Type/Etiology
    End point description
    For all reported bleeding events, the type and the etiology of the bleeding event were collected. Subjects who experienced bleeding events during the 'on-treatment period' were counted by bleeding type and etiology. Subjects who had multiple bleeding could be counted several times. The analysis was performed on the same population as previously (i.e. exposed population).
    End point type
    Secondary
    End point timeframe
    From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first
    End point values
    		 Placebo Clopidogrel 0.2 mg/kg/Day
    Number of subjects analysed
    436
    464
    Units: Subjects
        Spontaneous
    60
    56
        Post-traumatic
    6
    11
        Puncture (vascular access site)
    19
    9
        Surgical
    10
    17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from signature of the informed consent form up to the last visit regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    AEs that developed/worsened and deaths that occurred during ‘on treatment period’ (from randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever came first) are reported. All-cause deaths include cardiovascular deaths (primary efficacy endpoint) and non-cardiovascular deaths resulting from AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Clopidogrel matching placebo until primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or common study-end-date, whichever came first.

    Reporting group title
    Clopidogrel 0.2mg/kg/day
    Reporting group description
    		 Clopidogrel until the primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or the common study-end-date, whichever came first

    Serious adverse events
    		 Placebo Clopidogrel 0.2mg/kg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    196 / 436 (44.95%)
    234 / 464 (50.43%)
         number of deaths (all causes)
    56
    50
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Stenosis
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory Collapse
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic Shock
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Stenosis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena Cava Thrombosis
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Anorectal Operation
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteroneocystostomy
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular Event Prophylaxis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter Thrombosis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Related Complication
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Haemorrhage
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeling Abnormal
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puncture Site Haemorrhage
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 436 (0.69%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vessel Puncture Site Haematoma
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Milk Allergy
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diaphragmatic Paralysis
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    11 / 436 (2.52%)
    14 / 464 (3.02%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Oedema
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Stenosis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mediastinal Haematoma
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive Airways Disorder
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal Haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Artery Stenosis
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Congestion
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary Vein Occlusion
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Vein Stenosis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Arrest
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    3 / 436 (0.69%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    4 / 436 (0.92%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Fatigue
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal Stenosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheomalacia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Congestion
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Thickening
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspiration Bronchial
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Urine Present
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen Saturation Decreased
         subjects affected / exposed
    10 / 436 (2.29%)
    11 / 464 (2.37%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen Saturation Increased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Arterial Pressure Decreased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Arterial Pressure Increased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Increased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Breakage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug Toxicity
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding Tube Complication
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional Hernia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft Thrombosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Operative Haemorrhage
         subjects affected / exposed
    3 / 436 (0.69%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax Traumatic
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Haematoma
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    4 / 436 (0.92%)
    8 / 464 (1.72%)
         occurrences causally related to treatment / all
    1 / 4
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Vaccination Syndrome
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Fever
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Respiratory Distress
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Wound Complication
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural Complication
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural Site Reaction
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt Blood Flow Excessive
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt Malfunction
         subjects affected / exposed
    3 / 436 (0.69%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt Occlusion
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull Fracture
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt Stenosis
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suture Related Complication
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suture Rupture
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Pseudoaneurysm
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Dehiscence
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial Septal Defect
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coarctation Of The Aorta
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngomalacia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyloric Stenosis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Artery Stenosis Congenital
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    4 / 436 (0.92%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Disorder
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    5 / 436 (1.15%)
    6 / 464 (1.29%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    2 / 436 (0.46%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Perforation
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 436 (0.23%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Pseudoaneurysm
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    9 / 436 (2.06%)
    24 / 464 (5.17%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilatation Ventricular
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low Cardiac Output Syndrome
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal Arrhythmia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 436 (0.23%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Valve Stenosis
         subjects affected / exposed
    3 / 436 (0.69%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Dysfunction
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Extrasystoles
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid Valve Incompetence
         subjects affected / exposed
    3 / 436 (0.69%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Dysfunction
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clonic Convulsion
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsions Local
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Embolic Stroke
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Convulsion
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemic Encephalopathy
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic Stroke
         subjects affected / exposed
    0 / 436 (0.00%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Cerebral Infarction
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial Seizures
         subjects affected / exposed
    0 / 436 (0.00%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phrenic Nerve Paralysis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage Neonatal
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor Sucking Reflex
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Paralysis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Paresis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Deficiency Anaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated Intravascular Coagulation
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Middle Ear Inflammation
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 436 (0.23%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Stenosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Haemorrhagic
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    4 / 436 (0.92%)
    6 / 464 (1.29%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 436 (0.46%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    7 / 436 (1.61%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising Colitis
         subjects affected / exposed
    1 / 436 (0.23%)
    6 / 464 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal Perforation
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    3 / 436 (0.69%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis Intestinalis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-Tussive Vomiting
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 436 (1.15%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute Hepatic Failure
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis Diaper
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous Emphysema
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash Papular
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Prerenal Failure
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bladder Prolapse
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesicoureteric Reflux
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Sepsis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    12 / 436 (2.75%)
    15 / 464 (3.23%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 436 (0.23%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Bacterial
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Viral
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    4 / 436 (0.92%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Sepsis
         subjects affected / exposed
    4 / 436 (0.92%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Candida Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 436 (0.23%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear Infection
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal Bacteraemia
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal Sepsis
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis Adenovirus
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    14 / 436 (3.21%)
    24 / 464 (5.17%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis Caliciviral
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Rotavirus
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    4 / 436 (0.92%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus Infection
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision Site Infection
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    5 / 436 (1.15%)
    6 / 464 (1.29%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella Bacteraemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal Abscess
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    3 / 436 (0.69%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Aseptic
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Pneumococcal
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nosocomial Infection
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media Acute
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae Virus Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis Bacterial
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 436 (2.06%)
    21 / 464 (4.53%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 24
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia Escherichia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Influenzal
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Respiratory Syncytial Viral
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Cellulitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Wound Infection
         subjects affected / exposed
    2 / 436 (0.46%)
    7 / 464 (1.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    3 / 436 (0.69%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Bronchiolitis
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    3 / 436 (0.69%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    3 / 436 (0.69%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection Bacterial
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 436 (0.00%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 436 (0.92%)
    8 / 464 (1.72%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sepsis Syndrome
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal Sepsis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    4 / 464 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    13 / 436 (2.98%)
    11 / 464 (2.37%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    6 / 436 (1.38%)
    6 / 464 (1.29%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Diarrhoea
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    6 / 436 (1.38%)
    7 / 464 (1.51%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Rash
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Abscess
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 436 (0.23%)
    6 / 464 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure To Thrive
         subjects affected / exposed
    6 / 436 (1.38%)
    3 / 464 (0.65%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding Disorder Of Infancy Or Early Childhood
         subjects affected / exposed
    5 / 436 (1.15%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food Intolerance
         subjects affected / exposed
    3 / 436 (0.69%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Seizure
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic Acidosis
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Gain Poor
         subjects affected / exposed
    3 / 436 (0.69%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Clopidogrel 0.2mg/kg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 436 (22.02%)
    107 / 464 (23.06%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 436 (4.59%)
    24 / 464 (5.17%)
         occurrences all number
    26
    27
    Vomiting
         subjects affected / exposed
    18 / 436 (4.13%)
    32 / 464 (6.90%)
         occurrences all number
    21
    35
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    53 / 436 (12.16%)
    60 / 464 (12.93%)
         occurrences all number
    69
    72
    Nasopharyngitis
         subjects affected / exposed
    24 / 436 (5.50%)
    21 / 464 (4.53%)
         occurrences all number
    28
    31

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Sep 2008
    Following the FDA comments that stopping the trial for futility could reduce the chance of having interpretable results (especially if the benefit is lower than the 30% assumption of the protocol) or the possibility to have meaningful information in the label, it had been decided to remove the futility stopping boundaries for the 3 planned interim analyses of the protocol. This decision was endorsed by the Data Monitoring Committee of the study prior to performing the first interim analysis. Since the efficacy and futility boundaries were computed considering both boundaries simultaneously, the removal of the futility boundary resulted in minor changes to the previously proposed efficacy boundary. Consequently, the EFC5314/CLARINET protocol was amended to remove the futility stopping boundaries and to make subsequent changes to the efficacy stopping boundaries, final significance level, and required number of primary events. The required number of primary events needed for this event driven trial decreased slightly from 174 to 172, and the final significance level changed from 0.037 to 0.035.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23782178
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