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    Clinical Trial Results:
    A Randomised, Double-blind, Phase III Study to Compare the Efficacy and Safety of Cediranib (AZD2171) when added to 5-fluorouracil, Leucovorin and Oxaliplatin (FOLFOX) or Capecitabine and Oxaliplatin (XELOX) with the Efficacy and Safety of Placebo when added to FOLFOX or XELOX in Patients with Previously Untreated Metastatic Colorectal Cancer

    Summary
    EudraCT number
    2006-001194-14
    Trial protocol
    DE   CZ   HU   GB  
    Global end of trial date
    17 Aug 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Sep 2017
    First version publication date
    02 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D8480C00051
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00399035
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    132 Hills Road, Cambridge, United Kingdom, CB2 1PG
    Public contact
    Tsveta Milenkova, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Tsveta Milenkova, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Mar 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the efficacy of cediranib when added to FOLFOX or XELOX compared to the efficacy of FOLFOX or XELOX alone in patients with previously untreated metastatic CRC, by assessment of the co-primary endpoints of PFS and OS.
    Protection of trial subjects
    If toxicity is encountered, the dose of cediranib may be reduced or treatment with cediranib stopped (for a maximum of 14 days) until resolution of symptoms. At the discretion of the investigator, study treatment may be restarted. Within a patient, the dose of cediranib can be reduced up to two times; for those patients receiving 20 mg cediranib there will only be one active dose reduction to 15 mg.
    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: 54
    Country: Number of subjects enrolled
    Australia: 68
    Country: Number of subjects enrolled
    Brazil: 204
    Country: Number of subjects enrolled
    Bulgaria: 147
    Country: Number of subjects enrolled
    China: 192
    Country: Number of subjects enrolled
    Czech Republic: 108
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hungary: 118
    Country: Number of subjects enrolled
    India: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 47
    Country: Number of subjects enrolled
    Philippines: 48
    Country: Number of subjects enrolled
    Poland: 97
    Country: Number of subjects enrolled
    Switzerland: 24
    Country: Number of subjects enrolled
    Thailand: 21
    Country: Number of subjects enrolled
    United Kingdom: 57
    Worldwide total number of subjects
    1254
    EEA total number of subjects
    567
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    849
    From 65 to 84 years
    405
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Randomised=full analysis set: Cediranib 20mg=502, Cediranib 30mg=216, Placebo=358; Safety set: Cediranib 20mg=500, Cediranib 30mg=214, Placebo=358. Primary analysis and results reported for Cediranib 20mg vs placebo.

    Pre-assignment
    Screening details
    Cediranib 30mg discontinued after Phase II, Cediranib 20mg chosen for comparing with Placebo.1254 patients enrolled to the study, 1076 received study treatment; 2 patients didn't receive cediranib/placebo for Cediranib 20 mg, and 2 patients didn't receive cediranib/placebo for Cediranib 30 mg. The 4 patients that didn't receive drug are included.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cediranib 20 mg/day
    Arm description
    [Cediranib 20mg/day+FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.
    Arm type
    Experimental

    Investigational medicinal product name
    cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg orally once daily

    Arm title
    Cediranib 30 mg/day
    Arm description
    [Cediranib 30mg/day+FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.
    Arm type
    Experimental

    Investigational medicinal product name
    cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30mg orally once daily

    Arm title
    Placebo
    Arm description
    [Placebo +FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg orally once daily

    Number of subjects in period 1 [1]
    Cediranib 20 mg/day Cediranib 30 mg/day Placebo
    Started
    502
    216
    358
    Completed
    189
    58
    106
    Not completed
    313
    158
    252
         Severe non-compliance with protocol
    2
    1
    -
         Adverse event, serious fatal
    289
    141
    234
         Incorrect enrolment/eligib not fulfilled
    1
    -
    1
         Consent withdrawn by subject
    19
    15
    12
         Lost to follow-up
    2
    1
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1254 patients enrolled to the study described in worldwide recruitment section, 1076 randomised to study treatment and described in baseline, efficacy and safety sections.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cediranib 20 mg/day
    Reporting group description
    [Cediranib 20mg/day+FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.

    Reporting group title
    Cediranib 30 mg/day
    Reporting group description
    [Cediranib 30mg/day+FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.

    Reporting group title
    Placebo
    Reporting group description
    [Placebo +FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.

    Reporting group values
    Cediranib 20 mg/day Cediranib 30 mg/day Placebo Total
    Number of subjects
    502 216 358 1076
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    343 148 245 736
        From 65-84 years
    159 68 113 340
        85 years and over
    0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    57.8 ± 11.14 59.4 ± 10.69 57.2 ± 11.63 -
    Gender, Male/Female
    Gender at informed consent
    Units: participants
        Female
    203 93 146 442
        Male
    299 123 212 634

    End points

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    End points reporting groups
    Reporting group title
    Cediranib 20 mg/day
    Reporting group description
    [Cediranib 20mg/day+FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.

    Reporting group title
    Cediranib 30 mg/day
    Reporting group description
    [Cediranib 30mg/day+FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.

    Reporting group title
    Placebo
    Reporting group description
    [Placebo +FOLFOX/XELOX].2 FOLFOX regimens were chosen:FOLFOX4 or mFOLFOX6(repeated every 2 weeks.FOLFOX4:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 200mg/m2(or equivalent folinic acid preparation) by iv infusion over 2h on Day1 and Day2;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1 and Day2;5-FU 600 mg/m2 immediately after the 5-FU bolus dosed by continuous iv infusion over 22h on Day1 and Day2.mFOLFOX6:oxaliplatin 85mg/m2 dosed by iv infusion over 2h on Day1;leucovorin 400mg/m2(or equivalent folinic acid preparation)dosed iv over 2h on Day1;5-FU 400mg/m2 iv bolus immediately after completion of the oxaliplatin/leucovorin infusion on Day1,followed immediately by 5-FU 2400mg/m2 dosed by continuous iv infusion over 46h.XELOX:The XELOX regimen was to be repeated every 3 weeks:oxaliplatin 130mg/m2 dosed by iv infusion over 2h on Day1;capecitabine 1000mg/m2 orally twice daily on Days1 to 14.

    Primary: Progression-free survival

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    End point title
    Progression-free survival [1]
    End point description
    RECIST criteria defined as follows: Target lesions Complete Response (CR) Disappearance of all target lesions Partial Response (PR) At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD.Progressive Disease (PD) At least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded (either at baseline or at previous assessment since treatment began).Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Non-target lesions Complete Response (CR) Disappearance of all non-target lesions Non-Complete Response (non-CR/Non- Progression [non-PD]) Persistence of one or more non-target lesion or/and maintenance of tumour marker level above the normal limits. Progression (PD) Unequivocal progression of existing nontarget lesions.
    End point type
    Primary
    End point timeframe
    RECIST assessed at baseline every 6 weeks through to week 24 and 12 week thereafter through to progression or data cut off date of 21/03/10 whichever was earliest.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    502
    358
    Units: Months
        median (inter-quartile range (Q1-Q3))
    8.6 (5.5 to 12.1)
    8.2 (4.1 to 11.1)
    Statistical analysis title
    Cox PH model
    Statistical analysis description
    The effect of treatment was be estimated by the adjusted HR together with its 95% CI, which was calculated from a Cox PH model fitted with the following covariates: performance status, the chemotherapy received, a twolevel baseline liver function covariate and study phase covariate. The model will be fitted using SAS’s PROC PHREG using the Breslow method for ties.
    Comparison groups
    Cediranib 20 mg/day v Placebo
    Number of subjects included in analysis
    860
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0121 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    0.95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.98
    Notes
    [2] - Statistically significant
    Statistical analysis title
    Alternative censoring mechanism (FAS, ITT)
    Statistical analysis description
    The first sensitivity analysis considered all progression events regardless of whether they occurred after 2 or more consecutive non-evaluable visits, or after patients had received another cancer therapy prior to progression. The results of this analysis were consistent with the primary analysis, indicating that the choice of censoring mechanism in the primary analysis did not influence the overall results.
    Comparison groups
    Cediranib 20 mg/day v Placebo
    Number of subjects included in analysis
    860
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0183 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    0.95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.97
    Notes
    [3] - P-value estimated from log-rank test stratified by same factors used in Cox Proportional Hazards model
    Statistical analysis title
    Interval-censored approach (FAS, ITT)
    Statistical analysis description
    The interval-censored analysis, which compared the proportion of patients progressing during discrete time intervals post-randomisation, was also consistent with the primary analysis, indicating that there was no bias due to any differences in the frequency of assessments between treatment arms
    Comparison groups
    Cediranib 20 mg/day v Placebo
    Number of subjects included in analysis
    860
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0279
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    0.95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.98
    Statistical analysis title
    Central review (FAS, ITT)
    Statistical analysis description
    Another post-hoc analysis was done to assess the impact of primary tumour location (colon or rectal) on the treatment effect for PFS, as a slight imbalance was observed in primary tumour location: 57.4% of patients on the cediranib arm versus 64.8% on the placebo arm had primary colon cancer. The HR for site of primary tumour was not significant, indicating that it was not a prognostic factor (HR=0.98; 95% CI 0.84, 1.14) and when included in the model did not affect the treatment effect HR.
    Comparison groups
    Cediranib 20 mg/day v Placebo
    Number of subjects included in analysis
    860
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0307 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    0.95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.02
    Notes
    [4] - P-value estimated from log-rank test stratified by same factors used in Cox Proportional Hazards model

    Primary: Overall survival

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    End point title
    Overall survival [5]
    End point description
    Number of months from randomisation to the date of death from any cause
    End point type
    Primary
    End point timeframe
    Baseline through to date of death upto and including data cut off date of 21/03/10
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    502
    358
    Units: Months
        median (inter-quartile range (Q1-Q3))
    19.7 (11 to 36.1)
    18.9 (11 to 28.9)
    Statistical analysis title
    OS analysis
    Statistical analysis description
    At the time of the data-cut off, a total of 523 patients (60.8% of total study population) had died, indicating a mature OS data set. Median follow-up was 22 months (21.8 months on cediranib 20 mg, and 23.1 months on placebo); therefore, most censored patients were represented towards the latter part of the Kaplan-Meier curve. Once the actual number of events became known it was possible to calculate the exact significance level. Accounting for Type 1 error, p <0.0491 was significant for OS.
    Comparison groups
    Cediranib 20 mg/day v Placebo
    Number of subjects included in analysis
    860
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.5707 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    0.95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.12
    Notes
    [6] - P-value estimated from a Log-Rank test stratifying for performance status (0 or 1), chemotherapy received, baseline liver function, and study phase (randomised before or after dropping of the 30 mg arm).

    Secondary: Overall response rate

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    End point title
    Overall response rate [7]
    End point description
    Objective tumour response(defined as a confirmed response of CR or PR).The definition for a confirmed response was met when an initial RECIST response of PR/CR was confirmed at the next scheduled visit as a PR/CR according to an evaluable assessment.Intervening assessments of non-evaluable or stable disease were allowable as long as the initial RECIST response was confirmed.RECIST criteria defined as follows: Target lesions Complete Response(CR)Disappearance of all target lesions Partial Response (PR).At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. Progressive Disease (PD) At least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded (either at baseline or at previous assessment since treatment began).Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.Non-target lesions Complete Response (CR) Disappearance of all non-target lesi
    End point type
    Secondary
    End point timeframe
    Baseline through to date of death upto and including data cut off date of 21/03/10
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    502
    358
    Units: Participants
    254
    178
    No statistical analyses for this end point

    Secondary: Best percentage change in tumour size

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    End point title
    Best percentage change in tumour size [8]
    End point description
    Maximum percentage reduction or minimum percentage increase in tumour size where size is the sum of the longest diameters of the target lesions
    End point type
    Secondary
    End point timeframe
    Baseline through to date of death upto and including data cut off date of 21/03/10
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    474
    339
    Units: Percentage [change in tumour size (mm) ]
        arithmetic mean (standard deviation)
    -42.49 ± 28.139
    -40.61 ± 31.992
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    Duration of response [9]
    End point description
    Based on RECIST measurements taken throughout the study and best objective tumour response at the defined analysis cut-off point. Measured from the time the criteria for CR/PR are first met (whichever is recorded first) until the patient progresses or dies.
    End point type
    Secondary
    End point timeframe
    Treatment period from initial response up until data cut-off date of 21/03/10
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    254
    178
    Units: Months
        median (inter-quartile range (Q1-Q3))
    8.5 (5.9 to 12.7)
    6.9 (4.8 to 11)
    No statistical analyses for this end point

    Secondary: Rate of resection of liver metastases

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    End point title
    Rate of resection of liver metastases [10]
    End point description
    Number of patients undergoing liver resection, based on patients with liver disease at baseline
    End point type
    Secondary
    End point timeframe
    Post-randomisation until end of study
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    387
    271
    Units: Participants
    21
    17
    No statistical analyses for this end point

    Secondary: Time to wound healing complications

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    End point title
    Time to wound healing complications [11]
    End point description
    Number of days from post-randomisation surgery until wound healing complications
    End point type
    Secondary
    End point timeframe
    Post-randomisation until end of study
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint presented is observed during follow-up, but not observable at baseline, nor is a “change from baseline” calculation appropriate for this endpoint.
    End point values
    Cediranib 20 mg/day Placebo
    Number of subjects analysed
    94
    79
    Units: Days
        median (full range (min-max))
    18 (1 to 93)
    18 (0 to 114)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group title
    cediranib 30 mg
    Reporting group description
    cediranib 30 mg

    Reporting group title
    cediranib 20 mg
    Reporting group description
    cediranib 20 mg

    Serious adverse events
    Placebo cediranib 30 mg cediranib 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    105 / 358 (29.33%)
    94 / 214 (43.93%)
    204 / 500 (40.80%)
         number of deaths (all causes)
    234
    140
    289
         number of deaths resulting from adverse events
    5
    6
    5
    Vascular disorders
    AORTIC THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    2 / 214 (0.93%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMORAL ARTERY OCCLUSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    8 / 214 (3.74%)
    6 / 500 (1.20%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 8
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL EMBOLISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PHLEBITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENA CAVA THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BENIGN NEOPLASM OF SPINAL CORD
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PENIS CARCINOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL CANCER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    1 / 214 (0.47%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FOOD ALLERGY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERSENSITIVITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEATH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    2 / 214 (0.93%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    FATIGUE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    2 / 214 (0.93%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFUSION SITE IRRITATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    PERFORMANCE STATUS DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 358 (1.12%)
    2 / 214 (0.93%)
    5 / 500 (1.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERSONALITY CHANGE DUE TO A GENERAL MEDICAL CONDITION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    FEMALE GENITAL TRACT FISTULA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VAGINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    COMMINUTED FRACTURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL STOMA COMPLICATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OVERDOSE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERONEAL NERVE INJURY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL COMPLICATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 358 (1.12%)
    2 / 214 (0.93%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE HERNIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND COMPLICATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STENT OCCLUSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    UPPER LIMB FRACTURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URETERIC INJURY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND COMPLICATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND DEHISCENCE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    BILIRUBIN CONJUGATED INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIVER FUNCTION TEST ABNORMAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE LEFT VENTRICULAR FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    ANGINA PECTORIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    3 / 214 (1.40%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRADYCARDIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    CARDIAC FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    2 / 214 (0.93%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    CARDIOPULMONARY FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    CORONARY ARTERY DISEASE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    3 / 214 (1.40%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    MYOCARDIAL ISCHAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TACHYCARDIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR ARRHYTHMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR DYSFUNCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    0 / 214 (0.00%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COOMBS POSITIVE HAEMOLYTIC ANAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DISSEMINATED INTRAVASCULAR COAGULATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    4 / 214 (1.87%)
    4 / 500 (0.80%)
         occurrences causally related to treatment / all
    1 / 3
    5 / 5
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    GRANULOCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEUKOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LYMPHOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    0 / 214 (0.00%)
    7 / 500 (1.40%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 358 (1.96%)
    0 / 214 (0.00%)
    11 / 500 (2.20%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSAESTHESIA PHARYNX
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    4 / 500 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EPISTAXIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMOPTYSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HICCUPS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERVENTILATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LARYNGOSPASM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG INFILTRATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY ARTERY THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 358 (1.12%)
    4 / 214 (1.87%)
    10 / 500 (2.00%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 4
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    RESPIRATORY FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Nervous system disorders
    APHASIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CENTRAL NERVOUS SYSTEM LESION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    2 / 214 (0.93%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    CEREBRAL INFARCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONVULSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    4 / 500 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSARTHRIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENCEPHALOPATHY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GRAND MAL CONVULSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEMIPARESIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    METABOLIC ENCEPHALOPATHY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MONOPARESIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NERVOUS SYSTEM DISORDER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEURALGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUROLOGICAL SYMPTOM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PARAESTHESIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    RETINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RETINAL VEIN OCCLUSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL HERNIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    3 / 214 (1.40%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ASCITES
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLONIC OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    4 / 500 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    11 / 358 (3.07%)
    14 / 214 (6.54%)
    34 / 500 (6.80%)
         occurrences causally related to treatment / all
    13 / 13
    15 / 16
    35 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER PERFORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPHAGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL FISTULA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    3 / 214 (1.40%)
    4 / 500 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL NECROSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL PERFORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATEMESIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATOCHEZIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHOIDS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 358 (1.12%)
    1 / 214 (0.47%)
    5 / 500 (1.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS PARALYTIC
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL FISTULA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 358 (1.12%)
    3 / 214 (1.40%)
    8 / 500 (1.60%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL PERFORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MECHANICAL ILEUS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    MELAENA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MESENTERIC VEIN THROMBOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    3 / 214 (1.40%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PEPTIC ULCER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROCTALGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROCTOCOLITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    STOMATITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    3 / 214 (1.40%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBILEUS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    3 / 214 (1.40%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VARICES OESOPHAGEAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 358 (2.23%)
    5 / 214 (2.34%)
    7 / 500 (1.40%)
         occurrences causally related to treatment / all
    7 / 9
    4 / 5
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLANGITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLESTASIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATORENAL FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    HYPERBILIRUBINAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    JAUNDICE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    AZOTAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATURIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROTIC SYNDROME
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROTEINURIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    5 / 214 (2.34%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    RENAL FAILURE ACUTE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    2 / 214 (0.93%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    RENAL FAILURE CHRONIC
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URETERIC OBSTRUCTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URETHRAL STENOSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY BLADDER HAEMORRHAGE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    PETECHIAE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PURPURA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GROIN PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOTHYROIDISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    2 / 214 (0.93%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THYROIDITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    7 / 358 (1.96%)
    8 / 214 (3.74%)
    14 / 500 (2.80%)
         occurrences causally related to treatment / all
    7 / 8
    6 / 9
    12 / 16
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    DIABETES MELLITUS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERAMMONAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTRIGLYCERIDAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOPROTEINAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL WALL ABSCESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE SINUSITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AMOEBIASIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AMOEBIC DYSENTERY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS PERFORATED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLASTOCYSTIS INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CAMPYLOBACTER INTESTINAL INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CATHETER RELATED INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    1 / 214 (0.47%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CATHETER SEPSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CATHETER SITE INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    2 / 500 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CENTRAL LINE INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLOSTOMY INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DENGUE FEVER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    2 / 214 (0.93%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFECTED EPIDERMAL CYST
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG ABSCESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    1 / 214 (0.47%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS BACTERIAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORAL CANDIDIASIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 358 (2.23%)
    3 / 214 (1.40%)
    7 / 500 (1.40%)
         occurrences causally related to treatment / all
    4 / 8
    0 / 3
    4 / 8
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 3
    PYELONEPHRITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYOTHORAX
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SCROTAL ABSCESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    3 / 358 (0.84%)
    3 / 214 (1.40%)
    4 / 500 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    2 / 3
    1 / 1
    SEPTIC SHOCK
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    3 / 500 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    STAPHYLOCOCCAL SEPSIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    2 / 358 (0.56%)
    0 / 214 (0.00%)
    6 / 500 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    0 / 358 (0.00%)
    0 / 214 (0.00%)
    1 / 500 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    1 / 358 (0.28%)
    0 / 214 (0.00%)
    0 / 500 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo cediranib 30 mg cediranib 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    341 / 358 (95.25%)
    209 / 214 (97.66%)
    485 / 500 (97.00%)
    Vascular disorders
    HYPERTENSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    41 / 358 (11.45%)
    96 / 214 (44.86%)
    226 / 500 (45.20%)
         occurrences all number
    49
    128
    297
    PHLEBITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    18 / 358 (5.03%)
    7 / 214 (3.27%)
    19 / 500 (3.80%)
         occurrences all number
    20
    7
    24
    Immune system disorders
    DRUG HYPERSENSITIVITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    19 / 358 (5.31%)
    6 / 214 (2.80%)
    24 / 500 (4.80%)
         occurrences all number
    29
    7
    31
    General disorders and administration site conditions
    ASTHENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    45 / 358 (12.57%)
    32 / 214 (14.95%)
    74 / 500 (14.80%)
         occurrences all number
    64
    41
    114
    FATIGUE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    104 / 358 (29.05%)
    80 / 214 (37.38%)
    200 / 500 (40.00%)
         occurrences all number
    169
    133
    322
    OEDEMA PERIPHERAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    46 / 358 (12.85%)
    22 / 214 (10.28%)
    53 / 500 (10.60%)
         occurrences all number
    58
    34
    57
    PYREXIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    60 / 358 (16.76%)
    31 / 214 (14.49%)
    76 / 500 (15.20%)
         occurrences all number
    104
    54
    110
    Psychiatric disorders
    INSOMNIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    27 / 358 (7.54%)
    15 / 214 (7.01%)
    50 / 500 (10.00%)
         occurrences all number
    30
    19
    65
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    15 / 358 (4.19%)
    11 / 214 (5.14%)
    33 / 500 (6.60%)
         occurrences all number
    22
    13
    56
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    18 / 358 (5.03%)
    9 / 214 (4.21%)
    33 / 500 (6.60%)
         occurrences all number
    28
    12
    59
    PLATELET COUNT DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    17 / 358 (4.75%)
    6 / 214 (2.80%)
    33 / 500 (6.60%)
         occurrences all number
    26
    12
    54
    WEIGHT DECREASED
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    18 / 358 (5.03%)
    28 / 214 (13.08%)
    63 / 500 (12.60%)
         occurrences all number
    19
    30
    78
    Blood and lymphatic system disorders
    ANAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    43 / 358 (12.01%)
    24 / 214 (11.21%)
    40 / 500 (8.00%)
         occurrences all number
    61
    28
    51
    GRANULOCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    9 / 358 (2.51%)
    3 / 214 (1.40%)
    28 / 500 (5.60%)
         occurrences all number
    24
    14
    61
    LEUKOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    39 / 358 (10.89%)
    15 / 214 (7.01%)
    84 / 500 (16.80%)
         occurrences all number
    86
    34
    264
    NEUTROPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    75 / 358 (20.95%)
    49 / 214 (22.90%)
    138 / 500 (27.60%)
         occurrences all number
    182
    73
    421
    THROMBOCYTOPENIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    84 / 358 (23.46%)
    56 / 214 (26.17%)
    139 / 500 (27.80%)
         occurrences all number
    144
    85
    296
    Respiratory, thoracic and mediastinal disorders
    COUGH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    35 / 358 (9.78%)
    24 / 214 (11.21%)
    50 / 500 (10.00%)
         occurrences all number
    39
    31
    57
    DYSPHONIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    4 / 358 (1.12%)
    39 / 214 (18.22%)
    67 / 500 (13.40%)
         occurrences all number
    9
    46
    80
    DYSPNOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    24 / 358 (6.70%)
    14 / 214 (6.54%)
    29 / 500 (5.80%)
         occurrences all number
    26
    18
    31
    EPISTAXIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    31 / 358 (8.66%)
    37 / 214 (17.29%)
    63 / 500 (12.60%)
         occurrences all number
    42
    49
    86
    HICCUPS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 358 (2.23%)
    11 / 214 (5.14%)
    23 / 500 (4.60%)
         occurrences all number
    10
    11
    37
    OROPHARYNGEAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    6 / 358 (1.68%)
    12 / 214 (5.61%)
    28 / 500 (5.60%)
         occurrences all number
    6
    12
    35
    Nervous system disorders
    DIZZINESS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    23 / 358 (6.42%)
    19 / 214 (8.88%)
    52 / 500 (10.40%)
         occurrences all number
    29
    28
    63
    DYSAESTHESIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    11 / 358 (3.07%)
    13 / 214 (6.07%)
    16 / 500 (3.20%)
         occurrences all number
    18
    32
    19
    DYSGEUSIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    25 / 358 (6.98%)
    14 / 214 (6.54%)
    26 / 500 (5.20%)
         occurrences all number
    35
    17
    34
    HEADACHE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    34 / 358 (9.50%)
    35 / 214 (16.36%)
    70 / 500 (14.00%)
         occurrences all number
    60
    54
    111
    HYPOAESTHESIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    17 / 358 (4.75%)
    7 / 214 (3.27%)
    38 / 500 (7.60%)
         occurrences all number
    24
    7
    56
    NEUROPATHY PERIPHERAL
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    64 / 358 (17.88%)
    24 / 214 (11.21%)
    77 / 500 (15.40%)
         occurrences all number
    127
    46
    161
    PARAESTHESIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    85 / 358 (23.74%)
    49 / 214 (22.90%)
    97 / 500 (19.40%)
         occurrences all number
    174
    100
    180
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    89 / 358 (24.86%)
    45 / 214 (21.03%)
    141 / 500 (28.20%)
         occurrences all number
    158
    69
    260
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    19 / 358 (5.31%)
    6 / 214 (2.80%)
    27 / 500 (5.40%)
         occurrences all number
    20
    6
    37
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    78 / 358 (21.79%)
    32 / 214 (14.95%)
    134 / 500 (26.80%)
         occurrences all number
    126
    40
    199
    ABDOMINAL PAIN UPPER
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    28 / 358 (7.82%)
    24 / 214 (11.21%)
    58 / 500 (11.60%)
         occurrences all number
    38
    27
    85
    CONSTIPATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    78 / 358 (21.79%)
    34 / 214 (15.89%)
    85 / 500 (17.00%)
         occurrences all number
    124
    58
    117
    DIARRHOEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    165 / 358 (46.09%)
    147 / 214 (68.69%)
    346 / 500 (69.20%)
         occurrences all number
    339
    444
    1044
    DYSPEPSIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    20 / 358 (5.59%)
    18 / 214 (8.41%)
    35 / 500 (7.00%)
         occurrences all number
    25
    21
    45
    FLATULENCE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    12 / 358 (3.35%)
    4 / 214 (1.87%)
    27 / 500 (5.40%)
         occurrences all number
    12
    4
    27
    NAUSEA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    169 / 358 (47.21%)
    92 / 214 (42.99%)
    256 / 500 (51.20%)
         occurrences all number
    429
    217
    675
    STOMATITIS
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    48 / 358 (13.41%)
    59 / 214 (27.57%)
    118 / 500 (23.60%)
         occurrences all number
    73
    102
    187
    VOMITING
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    126 / 358 (35.20%)
    83 / 214 (38.79%)
    230 / 500 (46.00%)
         occurrences all number
    287
    187
    544
    Renal and urinary disorders
    PROTEINURIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    12 / 358 (3.35%)
    20 / 214 (9.35%)
    60 / 500 (12.00%)
         occurrences all number
    16
    40
    101
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    22 / 358 (6.15%)
    18 / 214 (8.41%)
    38 / 500 (7.60%)
         occurrences all number
    23
    20
    39
    DRY SKIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    11 / 358 (3.07%)
    14 / 214 (6.54%)
    16 / 500 (3.20%)
         occurrences all number
    11
    15
    18
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    57 / 358 (15.92%)
    53 / 214 (24.77%)
    123 / 500 (24.60%)
         occurrences all number
    87
    75
    167
    RASH
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    19 / 358 (5.31%)
    9 / 214 (4.21%)
    33 / 500 (6.60%)
         occurrences all number
    21
    13
    41
    SKIN HYPERPIGMENTATION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    25 / 358 (6.98%)
    9 / 214 (4.21%)
    34 / 500 (6.80%)
         occurrences all number
    26
    10
    35
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    14 / 358 (3.91%)
    15 / 214 (7.01%)
    34 / 500 (6.80%)
         occurrences all number
    14
    19
    46
    BACK PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    19 / 358 (5.31%)
    17 / 214 (7.94%)
    41 / 500 (8.20%)
         occurrences all number
    21
    21
    48
    MUSCULOSKELETAL PAIN
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    12 / 358 (3.35%)
    13 / 214 (6.07%)
    22 / 500 (4.40%)
         occurrences all number
    14
    15
    27
    PAIN IN EXTREMITY
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    14 / 358 (3.91%)
    14 / 214 (6.54%)
    48 / 500 (9.60%)
         occurrences all number
    14
    15
    61
    Endocrine disorders
    HYPOTHYROIDISM
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    8 / 358 (2.23%)
    28 / 214 (13.08%)
    42 / 500 (8.40%)
         occurrences all number
    8
    29
    43
    Metabolism and nutrition disorders
    DECREASED APPETITE
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    125 / 358 (34.92%)
    92 / 214 (42.99%)
    229 / 500 (45.80%)
         occurrences all number
    231
    155
    396
    HYPOKALAEMIA
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    22 / 358 (6.15%)
    19 / 214 (8.88%)
    58 / 500 (11.60%)
         occurrences all number
    37
    29
    95
    Infections and infestations
    URINARY TRACT INFECTION
    alternative dictionary used: MedDRA 17
         subjects affected / exposed
    14 / 358 (3.91%)
    15 / 214 (7.01%)
    40 / 500 (8.00%)
         occurrences all number
    15
    23
    62

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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