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    Clinical Trial Results:
    A Phase III, Randomised, Double-Blind, Multi-Centre Parallel-Group Study to Assess the Efficacy of Vandetanib (ZD6474, ZACTIMA™) Versus Erlotinib (TARCEVA®) in Patients With Locally Advanced or Metastatic (Stage IIIB – IV) Non-Small Cell Lung Cancer (NSCLC) after Failure of at least One Prior Cytotoxic Chemotherapy

    Summary
    EudraCT number
    2006-000259-16
    Trial protocol
    NL   DK   NO   ES   DE   IT   GB  
    Global end of trial date
    15 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2017
    First version publication date
    15 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4200C000057
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00364351
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street , Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    15 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate an improvement in Progression Free Survival (PFS) for vandetanib compared with erlotinib (Tarceva®) in subjects with locally advanced or metastatic NSCLC after failure of at least one but no more than two, prior cytotoxic chemotherapy regimens.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Aug 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: 34
    Country: Number of subjects enrolled
    Australia: 60
    Country: Number of subjects enrolled
    Brazil: 53
    Country: Number of subjects enrolled
    Canada: 58
    Country: Number of subjects enrolled
    China: 89
    Country: Number of subjects enrolled
    Hong Kong: 50
    Country: Number of subjects enrolled
    India: 32
    Country: Number of subjects enrolled
    Indonesia: 25
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Philippines: 38
    Country: Number of subjects enrolled
    Taiwan: 51
    Country: Number of subjects enrolled
    Thailand: 106
    Country: Number of subjects enrolled
    United States: 148
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    Norway: 37
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    United Kingdom: 112
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Italy: 86
    Worldwide total number of subjects
    1240
    EEA total number of subjects
    435
    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)
    789
    From 65 to 84 years
    448
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    First subject enrolled 24 August 2006, last subject enrolled 31 October 2007, cut off date 26 September 2008. 1574 subjects were enrolled in the study.

    Pre-assignment
    Screening details
    1574 subjects were enrolled/screened to the study but only 1240 subjects were entered treatment/randomized. Completed subjects refers to on going study treatment at data cut-off date 26 Sep 2008.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Vandetanib
    Arm description
    Vandetanib 300 mg tablet taken once daily plus a placebo for erlotinib.
    Arm type
    Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    ZD6474
    Other name
    ZACTIMA™
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vandetanib was administered each morning, at least 1 hour prior to or 2 hours after, intake of food.

    Investigational medicinal product name
    Placebo for Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for erlotinib was administered each morning, at least 1 hour prior to or 2 hours after, intake of food.

    Arm title
    Erlotinib
    Arm description
    Erlotinib 150 mg tablet taken once daily plus a placebo for vandetanib.
    Arm type
    Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Tarceva®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib was administered each morning, at least 1 hour prior to or 2 hours after, intake of food.

    Investigational medicinal product name
    Placebo for Vandetanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for vandetanib was administered each morning, at least 1 hour prior to or 2 hours after, intake of food.

    Number of subjects in period 1
    Vandetanib Erlotinib
    Started
    623
    617
    Completed
    31
    34
    Not completed
    592
    583
         Subject could not travel to site
    -
    1
         Poor treatment compliance
    -
    3
         Adverse event
    90
    44
         Prohibited concomitant medication
    -
    2
         Investigator error
    -
    2
         Consent withdrawn by subject
    30
    29
         Randomised treatment not started
    -
    3
         Condition under investigation worsened
    469
    497
         Sponsor decision
    1
    -
         Incorrect enrollment
    1
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vandetanib
    Reporting group description
    Vandetanib 300 mg tablet taken once daily plus a placebo for erlotinib.

    Reporting group title
    Erlotinib
    Reporting group description
    Erlotinib 150 mg tablet taken once daily plus a placebo for vandetanib.

    Reporting group values
    Vandetanib Erlotinib Total
    Number of subjects
    623 617 1240
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    60 (26 to 92) 61 (26 to 85) -
    Gender categorical
    Units: Subjects
        Female
    242 224 466
        Male
    381 393 774

    End points

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    End points reporting groups
    Reporting group title
    Vandetanib
    Reporting group description
    Vandetanib 300 mg tablet taken once daily plus a placebo for erlotinib.

    Reporting group title
    Erlotinib
    Reporting group description
    Erlotinib 150 mg tablet taken once daily plus a placebo for vandetanib.

    Primary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS) [1]
    End point description
    Median time (in weeks) from randomisation until objective disease progression or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable Response Evaluation Criteria In Solid Tumors (RECIST) assessment. Progression was derived according to RECIST 1.0 and is defined as an increase of at least 20% in the total tumour size of measurable lesions over the nadir measurement, unequivocal progression in the non-target lesions or the appearance of one or more new lesions.
    End point type
    Primary
    End point timeframe
    progressionRECIST tumour assessments carried out every 4 weeks up to week 16 then every 8 weeks thereafter from randomisation until the date of first documented objective disease progression or date of death from any cause, whichever came first, assessed
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were reported, inferential statistics were not planned to be reported for primary endpoint.
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: Weeks
        median (full range (min-max))
    11.3 (0.14 to 75.43)
    8.9 (0.43 to 80.43)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival is defined as the time from date of randomization until death. Any subject not known to have died at the time of analysis was censored based on the last recorded date on which the subject was known to be alive (i.e. their status must be known at the censored date and should not be lost to follow up or unknown).
    End point type
    Secondary
    End point timeframe
    Time to death in months
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: Months
        median (full range (min-max))
    6.9 (0.03 to 18.46)
    7.8 (0.10 to 20.04)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    The ORR is the number of subjects that are responders i.e. those subjects with a confirmed best objective response of complete response (CR) or partial response (PR) as determined according to RECIST 1.0. CR is defined as the disappearance of all target lesions with no evidence of tumour elsewhere and PR is defined as at least a 30% reduction in the total tumour size of measurable lesions with no new lesions and no progression in the non-target lesions.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments every 4 weeks up to week 16 then every 8 weeks thereafter from randomisation until the date of first documented objective disease progression or date of death from any cause, whichever came first, assessed up to 21 months
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: subjects
    75
    74
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    Disease Control Rate (DCR)
    End point description
    Disease control rate is defined as the number of subjects who achieved disease control at least 8 weeks following randomisation. Disease control is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) >=8 weeks as determined according to RECIST 1.0. CR is defined as the disappearance of all target lesions with no evidence of tumour elsewhere, PR is defined as at least a 30% reduction in the total tumour size of measurable lesions with no new lesions and no progression in the non-target lesions and SD >=8 is assigned to subjects who have not responded and have no evidence of progression at least 8 weeks after randomisation.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments carried out every 4 weeks until week 16 then every 8 weeks thereafter (+/-3 days) from randomisation until objective progression
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: subjects
    254
    242
    No statistical analyses for this end point

    Secondary: Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Pain

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    End point title
    Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Pain
    End point description
    Pain was assessed as the average score of two items: Question 9 ("Have you had pain") and 19 ("Did pain interfere with your daily activities") of the QLQ-C30. Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 28 days. A subject is defined as having a deterioration in symptoms if they have a single visit assessment of ‘worsened’ with no visit assessment of ‘improved’ within the next 28 days. Analysis was performed on FAS, which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Disease-related symptom assessments are to be administered at screening (within 7 days before the first dose of study medication), every 4 weeks thereafter, at discontinuation of study treatment and at the 30-day follow-up visit
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    11.1 (4.4 to 26)
    9.9 (4.3 to 24.3)
    No statistical analyses for this end point

    Secondary: Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Dyspnoea

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    End point title
    Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Dyspnoea
    End point description
    Dyspnea was assessed as the average score of four items: Question 8 of the QLQ-C30 ("Were you short of breath") and Question 3 of the QLQ-C30 ("Were you short of breath when you rested"), Questions 4 ("Were you short of breath when you walked") and 5 ("Were you short of breath when you climbed stairs") of the QLQ-LC13 (or, equivalently, Questions 33, 34 and 35 of the combined QLQ-C30 and QLQ-LC13 questionnaires). Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 28 days. A subject is defined as having a deterioration in symptoms if they have a single visit assessment of ‘worsened’ with no visit assessment of ‘improved’ within the next 28 days. Analysis was performed on FAS, which included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Disease-related symptom assessments are to be administered at screening (within 7 days before the first dose of study medication), every 4 weeks thereafter, at discontinuation of study treatment and at the 30-day follow-up visit
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    12 (5.7 to 29.7)
    12.4 (5.1 to 34.4)
    No statistical analyses for this end point

    Secondary: Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Cough

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    End point title
    Time to Deterioration of Disease-related Symptoms (TDS) by EORTC Quality of Life Questionnaire - Cough
    End point description
    Cough was assessed using Question 1 ("How much did you cough") of the QLQ-LC13 (or, equivalently, Question 31 of the combined QLQ-C30 and QLQ-LC13 questionnaires). Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 28 days. A subject is defined as having a deterioration in symptoms if they have a single visit assessment of ‘worsened’ with no visit assessment of ‘improved’ within the next 28 days.
    End point type
    Secondary
    End point timeframe
    Disease-related symptom assessments are to be administered at screening (within 7 days before the first dose of study medication), every 4 weeks thereafter, at discontinuation of study treatment and at the 30-day follow-up visit
    End point values
    Vandetanib Erlotinib
    Number of subjects analysed
    623
    617
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    15.6 (8.1 to 36.1)
    14.1 (7 to 37.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (up to 10 years) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    The Safety Analysis Set included all randomized subjects who received at least 1 dose of randomized treatment, 623 in vandetanib and 614 in erlotinib.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Vandetanib
    Reporting group description
    -

    Reporting group title
    Erlotinib
    Reporting group description
    Erlotinib.

    Serious adverse events
    Vandetanib Erlotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    197 / 623 (31.62%)
    155 / 614 (25.24%)
         number of deaths (all causes)
    413
    416
         number of deaths resulting from adverse events
    36
    18
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 623 (0.16%)
    5 / 614 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 623 (0.48%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 623 (0.00%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic Shock
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jugular Vein Thrombosis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian Vein Thrombosis
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Thoracotomy
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-Cell Small Lymphocytic Lymphoma
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer Pain
         subjects affected / exposed
    3 / 623 (0.48%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiosis Carcinomatosa
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Pleural Effusion
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Shock
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 623 (0.64%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    2 / 623 (0.32%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication Associated With Device
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 623 (0.48%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 623 (1.12%)
    6 / 614 (0.98%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 623 (0.16%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Confusional State
         subjects affected / exposed
    1 / 623 (0.16%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    2 / 623 (0.32%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Radiation
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation Injury
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Graft Occlusion
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-Reactive Protein Increased
         subjects affected / exposed
    0 / 623 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram St-T Change
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T Wave Inversion
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 623 (0.32%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    6 / 623 (0.96%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pericardial Effusion
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postinfarction Angina
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade De Pointes
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acquired Tracheo-Oesophageal Fistula
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthmatic Crisis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial Fistula
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    4 / 623 (0.64%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    13 / 623 (2.09%)
    20 / 614 (3.26%)
         occurrences causally related to treatment / all
    1 / 13
    3 / 20
         deaths causally related to treatment / all
    1 / 6
    1 / 2
    Haemoptysis
         subjects affected / exposed
    1 / 623 (0.16%)
    11 / 614 (1.79%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypoxia
         subjects affected / exposed
    0 / 623 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Oedema
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 623 (0.16%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural Fibrosis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    2 / 623 (0.32%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 623 (0.32%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 623 (0.00%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    8 / 623 (1.28%)
    6 / 614 (0.98%)
         occurrences causally related to treatment / all
    4 / 8
    1 / 6
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 623 (0.16%)
    5 / 614 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    4 / 623 (0.64%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 623 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic Thrombocytopenic Purpura
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Altered State Of Consciousness
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aphasia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Thrombosis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 623 (0.16%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Dizziness
         subjects affected / exposed
    3 / 623 (0.48%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paralysis Recurrent Laryngeal Nerve
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor Hyperactivity
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    7 / 623 (1.12%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 623 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech Disorder
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 623 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 623 (0.16%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ulcerative Keratitis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    4 / 623 (0.64%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Wall Haematoma
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    19 / 623 (3.05%)
    8 / 614 (1.30%)
         occurrences causally related to treatment / all
    10 / 19
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 623 (0.64%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia Strangulated
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 623 (0.80%)
    5 / 614 (0.81%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Stenosis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    9 / 623 (1.44%)
    9 / 614 (1.47%)
         occurrences causally related to treatment / all
    3 / 9
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Colic
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial Nephritis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis Acneiform
         subjects affected / exposed
    0 / 623 (0.00%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis Exfoliative
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema Asteatotic
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema Multiforme
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Photosensitivity Reaction
         subjects affected / exposed
    3 / 623 (0.48%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    7 / 623 (1.12%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    7 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash Erythematous
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash Papular
         subjects affected / exposed
    0 / 623 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 623 (0.00%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 623 (0.16%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    0 / 623 (0.00%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Decreased Appetite
         subjects affected / exposed
    3 / 623 (0.48%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    7 / 623 (1.12%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 623 (0.32%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Colitis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Clostridial
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Genital Infection
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary Infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective Exacerbation Of Chronic Obstructive Airways Disease
         subjects affected / exposed
    2 / 623 (0.32%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    7 / 623 (1.12%)
    6 / 614 (0.98%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung Infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterial Infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Infection
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Infection Bacterial
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal Sepsis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    27 / 623 (4.33%)
    22 / 614 (3.58%)
         occurrences causally related to treatment / all
    1 / 27
    2 / 22
         deaths causally related to treatment / all
    0 / 9
    1 / 5
    Pneumonia Haemophilus
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    2 / 623 (0.32%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 623 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    5 / 623 (0.80%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 623 (0.16%)
    4 / 614 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 623 (0.16%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Streptococcal Bacteraemia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    6 / 623 (0.96%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Vandetanib Erlotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    539 / 623 (86.52%)
    542 / 614 (88.27%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    99 / 623 (15.89%)
    14 / 614 (2.28%)
         occurrences all number
    102
    17
    Investigations
    Weight Decreased
         subjects affected / exposed
    33 / 623 (5.30%)
    29 / 614 (4.72%)
         occurrences all number
    33
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    78 / 623 (12.52%)
    92 / 614 (14.98%)
         occurrences all number
    84
    105
    Dyspnoea
         subjects affected / exposed
    84 / 623 (13.48%)
    70 / 614 (11.40%)
         occurrences all number
    87
    75
    Haemoptysis
         subjects affected / exposed
    31 / 623 (4.98%)
    39 / 614 (6.35%)
         occurrences all number
    32
    45
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    37 / 623 (5.94%)
    40 / 614 (6.51%)
         occurrences all number
    39
    46
    Headache
         subjects affected / exposed
    55 / 623 (8.83%)
    40 / 614 (6.51%)
         occurrences all number
    55
    44
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    50 / 623 (8.03%)
    59 / 614 (9.61%)
         occurrences all number
    58
    65
    Fatigue
         subjects affected / exposed
    119 / 623 (19.10%)
    109 / 614 (17.75%)
         occurrences all number
    123
    119
    Oedema Peripheral
         subjects affected / exposed
    21 / 623 (3.37%)
    34 / 614 (5.54%)
         occurrences all number
    21
    35
    Pyrexia
         subjects affected / exposed
    44 / 623 (7.06%)
    50 / 614 (8.14%)
         occurrences all number
    51
    53
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    59 / 623 (9.47%)
    40 / 614 (6.51%)
         occurrences all number
    60
    40
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    58 / 623 (9.31%)
    87 / 614 (14.17%)
         occurrences all number
    63
    92
    Diarrhoea
         subjects affected / exposed
    300 / 623 (48.15%)
    232 / 614 (37.79%)
         occurrences all number
    450
    347
    Dyspepsia
         subjects affected / exposed
    29 / 623 (4.65%)
    31 / 614 (5.05%)
         occurrences all number
    31
    31
    Nausea
         subjects affected / exposed
    138 / 623 (22.15%)
    131 / 614 (21.34%)
         occurrences all number
    157
    158
    Stomatitis
         subjects affected / exposed
    33 / 623 (5.30%)
    33 / 614 (5.37%)
         occurrences all number
    33
    36
    Vomiting
         subjects affected / exposed
    85 / 623 (13.64%)
    91 / 614 (14.82%)
         occurrences all number
    108
    113
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    33 / 623 (5.30%)
    8 / 614 (1.30%)
         occurrences all number
    37
    9
    Skin and subcutaneous tissue disorders
    Dermatitis Acneiform
         subjects affected / exposed
    75 / 623 (12.04%)
    103 / 614 (16.78%)
         occurrences all number
    80
    117
    Acne
         subjects affected / exposed
    45 / 623 (7.22%)
    50 / 614 (8.14%)
         occurrences all number
    49
    59
    Dry Skin
         subjects affected / exposed
    60 / 623 (9.63%)
    84 / 614 (13.68%)
         occurrences all number
    62
    91
    Pruritus
         subjects affected / exposed
    38 / 623 (6.10%)
    67 / 614 (10.91%)
         occurrences all number
    41
    78
    Rash
         subjects affected / exposed
    169 / 623 (27.13%)
    232 / 614 (37.79%)
         occurrences all number
    198
    262
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    37 / 623 (5.94%)
    40 / 614 (6.51%)
         occurrences all number
    39
    44
    Musculoskeletal Chest Pain
         subjects affected / exposed
    33 / 623 (5.30%)
    24 / 614 (3.91%)
         occurrences all number
    36
    24
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    114 / 623 (18.30%)
    123 / 614 (20.03%)
         occurrences all number
    125
    127
    Infections and infestations
    Paronychia
         subjects affected / exposed
    12 / 623 (1.93%)
    31 / 614 (5.05%)
         occurrences all number
    12
    36

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2006
    Added option to continue blinded vandetanib/erlotinib after progression.
    23 Apr 2007
    Subjects receiving medications at study entry on a specific list in the protocol, that have a risk of QTc prolongation but no clear association with torsade de pointes, were allowed to continue those medications. Subjects receiving these medications were excluded if the screening QTc is ≥460 ms, and an additional ECG was obtained 4–8 h after the first dose of vandetanib.
    23 Apr 2007
    Exclusion criterion for serum creatinine >1.5 x ULRR or creatinine clearance ≤50 mL/min changed to creatinine clearance ≤30 mL/min.
    19 Mar 2008
    Removed co-primary analysis population.

    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.
    Primary results are complemented by Sanofi following sponsorship transfer from Astra Zeneca to Sanofi in May 2016, only SAEs are updated per protocol.
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