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    Clinical Trial Results:
    A Phase III, Randomized, Double-blinded, Parallel Group, Multi-centre Study to Assess the Efficacy and Safety of ZD6474 (ZACTIMA™) in Combination with Pemetrexed (Alimta®) versus Pemetrexed alone in Patients with Locally-Advanced or Metastatic (stage IIIB or IV) Non-Small Cell Lung Cancer (NSCLC) after Failure of 1st Line Anti-cancer Therapy

    Summary
    EudraCT number
    		 2006-003695-35
    Trial protocol
    		 SE   DE   GR   PT   IT   BE   GB   ES   FR  
    Global end of trial date
    14 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2025
    First version publication date
    18 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4200C00036
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00418886
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sanofi: LPS15296
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    50 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi-Aventis Recherche & Developpement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    05 Sep 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2023
    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) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, for the combination of vandetanib plus pemetrexed compared with pemetrexed plus placebo in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of first line anti-cancer therapy (not including an adjuvant regimen).
    Protection of trial subjects
    Participants 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 participant and considering the local culture. During the course of the trial, participants were provided with individual participant cards indicating the nature of the trial the participant 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
    09 Jan 2007
    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: 20
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Colombia: 10
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    India: 2
    Country: Number of subjects enrolled
    Israel: 61
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Mexico: 29
    Country: Number of subjects enrolled
    Philippines: 28
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    South Africa: 36
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 10
    Worldwide total number of subjects
    534
    EEA total number of subjects
    184
    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)
    370
    From 65 to 84 years
    164
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a parallel-group, placebo-controlled study. First participant enrolled 09 January 2007, last participant enrolled 29 February 2008, cut off date 05 September 2008.

    Pre-assignment
    Screening details
    		 A total of 534 participants were randomized in the study. Of which, 124 participants from vandetanib group and 110 participants from placebo group completed or discontinued treatment in randomized period entered survival follow-up period. All participants entered survival follow-up period completed end of treatment or died due to any cause.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vandetanib Plus Pemetrexed
    Arm description
    		 Vandetanib [100 milligram (mg) daily] plus pemetrexed [500 mg/metre square (m^2) given on Day 1 of each 21-day cycle].
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    Other name
    ZD6474, ZACTIMA™
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vandetanib 100 mg oral tablet administered daily in each 21-day cycle.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m^2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

    Arm title
    		 Placebo Plus Pemetrexed
    Arm description
    		 Placebo plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle).
    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
    Placebo oral tablet administered daily in each 21-day cycle.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m^2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    		Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Started
    256
    278
    Completed
    30
    23
    Not completed
    226
    255
         Consent withdrawn by subject
    9
    10
         Death
    122
    147
         Randomised but no treatment received
    -
    1
         Withdrawn due to other reason
    1
    -
         Discontinue treatment survival follow-up
    90
    91
         Lost to follow-up
    4
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vandetanib Plus Pemetrexed
    Reporting group description
    		 Vandetanib [100 milligram (mg) daily] plus pemetrexed [500 mg/metre square (m^2) given on Day 1 of each 21-day cycle].

    Reporting group title
    Placebo Plus Pemetrexed
    Reporting group description
    		 Placebo plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle).

    Reporting group values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed Total
    Number of subjects
    		 256 278 534
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.7 ( 9.95 ) 60.2 ( 9.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 97 107 204
        Male
    		 159 171 330

    End points

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    End points reporting groups
    Reporting group title
    Vandetanib Plus Pemetrexed
    Reporting group description
    		 Vandetanib [100 milligram (mg) daily] plus pemetrexed [500 mg/metre square (m^2) given on Day 1 of each 21-day cycle].

    Reporting group title
    Placebo Plus Pemetrexed
    Reporting group description
    		 Placebo plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle).

    Primary: Progression-Free Survival in the Overall Population

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    End point title
    		 Progression-Free Survival in the Overall Population [1]
    End point description
    Median time (in weeks) from randomization 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 RECIST assessment. The full analysis set included all randomized participants.
    End point type
    Primary
    End point timeframe
    RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression.
    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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: weeks
        median (confidence interval 95%)
    17.6 (13.4 to 18.9)
    11.9 (11.4 to 15.9)
    No statistical analyses for this end point

    Primary: Progression-Free Survival in the Female Population

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    End point title
    		 Progression-Free Survival in the Female Population [2]
    End point description
    Median time (in weeks) from randomization 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 RECIST assessment. The female analysis set included all randomized female participants.
    End point type
    Primary
    End point timeframe
    RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression.
    Notes
    [2] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    97
    107
    Units: weeks
        median (confidence interval 95%)
    17.9 (14.7 to 22.7)
    13.0 (11.1 to 17.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The OS is defined as the time from date of randomization until death. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant 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). The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Time to death in months
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: months
        median (confidence interval 95%)
    10.5 (8.9 to 12.3)
    9.2 (7.1 to 12.0)
    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 participants that are responders i.e, those participants with a confirmed best objective response of complete response (CR) or partial response (PR) as defined by RECIST criteria. The categories for best objective response are CR, PR, stable disease (SD)>= 6 weeks, progressive disease (PD) or NE. The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Each participant was assessed for objective response from the sequence of RECIST scan data up to data cut off. RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: percentage of participants
        number (not applicable)
    19.1
    7.9
    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
    The DCR is defined as the number of patients who achieved disease control at 6 weeks following randomization. Disease control at 6 weeks is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) >= 6 weeks. The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: percentage of participants
        number (not applicable)
    56.6
    45.7
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Response is defined as a confirmed best objective response of CR or PR. Duration of response is defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression (provided death is within 3 months of last RECIST assessment). The full analysis set included all randomized participants. Only participants with response are analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    49
    22
    Units: weeks
        median (confidence interval 95%)
    24.1 (17.4 to 30.0)
    24.4 (18.0 to 32.0)
    No statistical analyses for this end point

    Secondary: Time to Deterioration of Disease-related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score

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    End point title
    		 Time to Deterioration of Disease-related Symptoms (TDS) by Lung Cancer Symptom Scale (LCSS) Total Score
    End point description
    TDS is the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of ‘worsened’ with no visit assessment of ‘improved’ within the next 21 days. The LCSS scale measures changes in symptoms associated with lung cancer. The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    LCSS questionnaires are to be administered every 3 weeks after randomization
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: weeks
        median (confidence interval 95%)
    18.1 (15.1 to 23.6)
    12.1 (9.7 to 17.3)
    No statistical analyses for this end point

    Secondary: Time to Deterioration of Disease-related Symptoms by Average Symptom Burden Index (ASBI) Score

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    End point title
    		 Time to Deterioration of Disease-related Symptoms by Average Symptom Burden Index (ASBI) Score
    End point description
    Time to deterioration is defined as the interval from the date of randomization to the first assessment of worsened without an improvement in the next 21 days. A deterioration in symptoms is defined as a single visit assessment of ‘worsened’ with no visit assessment of ‘improved’ within the next 21 days. The ASBI is derived from 6 of LCSS’s 9 items. The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    ASBI is a score taken from the LCSS questionnaires which are to be administered every 3 weeks after randomization
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: weeks
        median (confidence interval 95%)
    16.0 (14.0 to 20.3)
    13.4 (10.3 to 17.9)
    No statistical analyses for this end point

    Secondary: Longitudinal Analysis of Lung Cancer Symptom Scale Total Score

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    End point title
    		 Longitudinal Analysis of Lung Cancer Symptom Scale Total Score
    End point description
    The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. LCSS total score is an average of all 9 visual analogue participant scales from "none" [0 millimeter (mm)] to "as much as it could be" (100 mm). The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    LCSS questionnaires are to be administered every 3 weeks after randomization
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: mms on a visual analogue scale
        least squares mean (standard error)
    25.7 ( 2.85 )
    28.3 ( 2.77 )
    No statistical analyses for this end point

    Secondary: Longitudinal Analysis of Average Symptom Burden Index Score

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    End point title
    		 Longitudinal Analysis of Average Symptom Burden Index Score
    End point description
    The longitudinal data analysis will include all non-missing visit scores and the model will include only the first 12 weeks of data. ASBI is an average of the 6 symptom visual analogue patient scales from "none" (0 mm) to "as much as it could be" (100 mm). The full analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    ASBI is a score taken from the LCSS questionnaires administered every 3 weeks after randomization
    End point values
    		 Vandetanib Plus Pemetrexed Placebo Plus Pemetrexed
    Number of subjects analysed
    256
    278
    Units: mms on a visual analogue scale
        least squares mean (standard error)
    21.7 ( 2.75 )
    24.3 ( 2.67 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of informed consent up to the study completion for each participant, approximately 193 months.
    Adverse event reporting additional description
    Analysis was performed on safety analysis set. 4 participants randomized to "Placebo Plus Pemetrexed" reporting group were erroneously assigned to receive vandetanib during Randomized Period. Therefore, total number of participants received “Vandetanib Plus pemetrexed” was 260 and "Placebo Plus Pemetrexed" was 273 during Randomized Period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0-25.1
    Reporting groups
    Reporting group title
    Randomized Period: Vandetanib Plus Pemetrexed
    Reporting group description
    		 Vandetanib (100 mg daily) plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle) in randomized period.

    Reporting group title
    Randomized Period: Placebo Plus Pemetrexed
    Reporting group description
    		 Placebo plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle) in randomized period.

    Reporting group title
    Survival Follow-up Period: Vandetanib Plus Pemetrexed
    Reporting group description
    		 Vandetanib (100 mg daily) plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle) in survival follow-up period.

    Reporting group title
    Survival Follow-up Period: Placebo Plus Pemetrexed
    Reporting group description
    		 Placebo plus pemetrexed (500 mg/m^2 given on Day 1 of each 21-day cycle) in survival follow-up period.

    Serious adverse events
    		 Randomized Period: Vandetanib Plus Pemetrexed Randomized Period: Placebo Plus Pemetrexed Survival Follow-up Period: Vandetanib Plus Pemetrexed Survival Follow-up Period: Placebo Plus Pemetrexed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    84 / 260 (32.31%)
    94 / 273 (34.43%)
    7 / 124 (5.65%)
    3 / 110 (2.73%)
         number of deaths (all causes)
    122
    147
    63
    58
         number of deaths resulting from adverse events
    2
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena Cava Thrombosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 260 (2.69%)
    3 / 273 (1.10%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organ Failure
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait Disturbance
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 260 (0.38%)
    6 / 273 (2.20%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alveolitis Allergic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Fistula
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    3 / 260 (1.15%)
    6 / 273 (2.20%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 273 (1.10%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 273 (1.47%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 260 (0.77%)
    3 / 273 (1.10%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 260 (3.08%)
    10 / 273 (3.66%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    1 / 10
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 273 (0.73%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaesthetic Complication Cardiac
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    2 / 260 (0.77%)
    4 / 273 (1.47%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic Valve Incompetence
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 273 (0.00%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Artery Embolism
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 273 (0.00%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphasia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 260 (0.77%)
    7 / 273 (2.56%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 260 (0.77%)
    5 / 273 (1.83%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 273 (1.47%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal Detachment
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual Impairment
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 260 (0.77%)
    4 / 273 (1.47%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Ulcer Haemorrhage
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reflux Oesophagitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 260 (1.15%)
    6 / 273 (2.20%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pemphigoid
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Photosensitivity Reaction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Prerenal Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal Insufficiency
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 273 (1.10%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 273 (0.00%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter Related Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 260 (2.69%)
    10 / 273 (3.66%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 13
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    4 / 260 (1.54%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 273 (0.00%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 273 (0.73%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 273 (0.00%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 273 (0.37%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized Period: Vandetanib Plus Pemetrexed Randomized Period: Placebo Plus Pemetrexed Survival Follow-up Period: Vandetanib Plus Pemetrexed Survival Follow-up Period: Placebo Plus Pemetrexed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    234 / 260 (90.00%)
    242 / 273 (88.64%)
    22 / 124 (17.74%)
    19 / 110 (17.27%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    14 / 260 (5.38%)
    21 / 273 (7.69%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    18
    24
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 260 (11.15%)
    8 / 273 (2.93%)
    2 / 124 (1.61%)
    1 / 110 (0.91%)
         occurrences all number
    35
    9
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 260 (11.15%)
    43 / 273 (15.75%)
    4 / 124 (3.23%)
    2 / 110 (1.82%)
         occurrences all number
    34
    63
    4
    2
    Fatigue
         subjects affected / exposed
    99 / 260 (38.08%)
    118 / 273 (43.22%)
    2 / 124 (1.61%)
    2 / 110 (1.82%)
         occurrences all number
    127
    159
    2
    2
    Oedema Peripheral
         subjects affected / exposed
    11 / 260 (4.23%)
    22 / 273 (8.06%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences all number
    12
    24
    1
    0
    Pyrexia
         subjects affected / exposed
    25 / 260 (9.62%)
    43 / 273 (15.75%)
    2 / 124 (1.61%)
    1 / 110 (0.91%)
         occurrences all number
    32
    60
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    18 / 260 (6.92%)
    6 / 273 (2.20%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences all number
    18
    6
    0
    1
    Cough
         subjects affected / exposed
    66 / 260 (25.38%)
    59 / 273 (21.61%)
    4 / 124 (3.23%)
    3 / 110 (2.73%)
         occurrences all number
    75
    68
    4
    3
    Dyspnoea
         subjects affected / exposed
    49 / 260 (18.85%)
    56 / 273 (20.51%)
    2 / 124 (1.61%)
    1 / 110 (0.91%)
         occurrences all number
    53
    60
    2
    1
    Epistaxis
         subjects affected / exposed
    17 / 260 (6.54%)
    12 / 273 (4.40%)
    1 / 124 (0.81%)
    1 / 110 (0.91%)
         occurrences all number
    22
    15
    2
    1
    Haemoptysis
         subjects affected / exposed
    12 / 260 (4.62%)
    17 / 273 (6.23%)
    1 / 124 (0.81%)
    1 / 110 (0.91%)
         occurrences all number
    14
    21
    1
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 260 (4.23%)
    16 / 273 (5.86%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    12
    16
    0
    0
    Depression
         subjects affected / exposed
    14 / 260 (5.38%)
    17 / 273 (6.23%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    14
    17
    0
    0
    Insomnia
         subjects affected / exposed
    34 / 260 (13.08%)
    27 / 273 (9.89%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences all number
    38
    27
    0
    1
    Investigations
    Weight Decreased
         subjects affected / exposed
    23 / 260 (8.85%)
    15 / 273 (5.49%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    23
    15
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 260 (7.69%)
    23 / 273 (8.42%)
    0 / 124 (0.00%)
    4 / 110 (3.64%)
         occurrences all number
    26
    30
    0
    5
    Headache
         subjects affected / exposed
    28 / 260 (10.77%)
    40 / 273 (14.65%)
    1 / 124 (0.81%)
    3 / 110 (2.73%)
         occurrences all number
    35
    50
    1
    4
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    18 / 260 (6.92%)
    17 / 273 (6.23%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    27
    22
    0
    0
    Neutropenia
         subjects affected / exposed
    21 / 260 (8.08%)
    26 / 273 (9.52%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    32
    35
    0
    0
    Anaemia
         subjects affected / exposed
    19 / 260 (7.31%)
    54 / 273 (19.78%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences all number
    27
    59
    0
    1
    Eye disorders
    Lacrimation Increased
         subjects affected / exposed
    12 / 260 (4.62%)
    14 / 273 (5.13%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    12
    16
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    16 / 260 (6.15%)
    15 / 273 (5.49%)
    1 / 124 (0.81%)
    2 / 110 (1.82%)
         occurrences all number
    21
    17
    1
    3
    Abdominal Pain Upper
         subjects affected / exposed
    14 / 260 (5.38%)
    17 / 273 (6.23%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    16
    18
    0
    0
    Constipation
         subjects affected / exposed
    52 / 260 (20.00%)
    53 / 273 (19.41%)
    3 / 124 (2.42%)
    0 / 110 (0.00%)
         occurrences all number
    69
    65
    3
    0
    Diarrhoea
         subjects affected / exposed
    66 / 260 (25.38%)
    48 / 273 (17.58%)
    3 / 124 (2.42%)
    2 / 110 (1.82%)
         occurrences all number
    95
    66
    3
    2
    Dyspepsia
         subjects affected / exposed
    21 / 260 (8.08%)
    11 / 273 (4.03%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences all number
    25
    11
    1
    0
    Nausea
         subjects affected / exposed
    73 / 260 (28.08%)
    98 / 273 (35.90%)
    0 / 124 (0.00%)
    3 / 110 (2.73%)
         occurrences all number
    100
    167
    0
    12
    Stomatitis
         subjects affected / exposed
    19 / 260 (7.31%)
    18 / 273 (6.59%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    25
    24
    0
    0
    Vomiting
         subjects affected / exposed
    37 / 260 (14.23%)
    55 / 273 (20.15%)
    3 / 124 (2.42%)
    3 / 110 (2.73%)
         occurrences all number
    42
    97
    3
    10
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    14 / 260 (5.38%)
    8 / 273 (2.93%)
    2 / 124 (1.61%)
    0 / 110 (0.00%)
         occurrences all number
    14
    9
    2
    0
    Acne
         subjects affected / exposed
    14 / 260 (5.38%)
    8 / 273 (2.93%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences all number
    15
    8
    1
    0
    Rash
         subjects affected / exposed
    99 / 260 (38.08%)
    71 / 273 (26.01%)
    3 / 124 (2.42%)
    1 / 110 (0.91%)
         occurrences all number
    143
    93
    5
    1
    Pruritus
         subjects affected / exposed
    28 / 260 (10.77%)
    40 / 273 (14.65%)
    0 / 124 (0.00%)
    1 / 110 (0.91%)
         occurrences all number
    37
    47
    0
    1
    Erythema
         subjects affected / exposed
    14 / 260 (5.38%)
    12 / 273 (4.40%)
    1 / 124 (0.81%)
    0 / 110 (0.00%)
         occurrences all number
    18
    16
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 260 (3.46%)
    16 / 273 (5.86%)
    2 / 124 (1.61%)
    3 / 110 (2.73%)
         occurrences all number
    10
    17
    2
    3
    Back Pain
         subjects affected / exposed
    24 / 260 (9.23%)
    31 / 273 (11.36%)
    1 / 124 (0.81%)
    2 / 110 (1.82%)
         occurrences all number
    25
    32
    1
    2
    Musculoskeletal Chest Pain
         subjects affected / exposed
    18 / 260 (6.92%)
    21 / 273 (7.69%)
    2 / 124 (1.61%)
    3 / 110 (2.73%)
         occurrences all number
    21
    26
    2
    4
    Musculoskeletal Pain
         subjects affected / exposed
    11 / 260 (4.23%)
    23 / 273 (8.42%)
    1 / 124 (0.81%)
    1 / 110 (0.91%)
         occurrences all number
    12
    25
    1
    1
    Pain In Extremity
         subjects affected / exposed
    13 / 260 (5.00%)
    18 / 273 (6.59%)
    0 / 124 (0.00%)
    4 / 110 (3.64%)
         occurrences all number
    13
    18
    0
    4
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    12 / 260 (4.62%)
    14 / 273 (5.13%)
    0 / 124 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    14
    19
    0
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    56 / 260 (21.54%)
    65 / 273 (23.81%)
    3 / 124 (2.42%)
    1 / 110 (0.91%)
         occurrences all number
    72
    82
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jan 2007
    • Phase II data suggested a more pronounced benefit for vandetanib in combination with chemotherapy compared with chemotherapy alone in female participants. • To allow participants receiving medications listed in Appendix D, that could not be discontinued, to continue those medications with additional safety precautions. • The per-protocol analysis was to exclude significant protocol deviators.
    13 Apr 2007
    • Sample size adjusted to allow for a single interim analysis to assess superiority of PFS and OS. • Renal impairment study showed no significant change in exposure for participants with mild or moderate renal impairment; creatinine clearance < 50 milliliter per minute excluded because of concomitant pemetrexed.
    17 Dec 2008
    • Participants continued to follow for survival due to a regulatory request to review further survival information. A further PFS analysis was not anticipated, however maintaining the RECIST schedule for ongoing participants was important to ensure no differential management of participants in terms of duration of treatment as this had a potential to impact the subsequent overall survival analysis. • In addition any participants still receiving vandetanib/placebo should continue to have all safety assessment performed as they were still receiving an investigational product. • No further quality of life or biomarker analyses was performed so it was not necessary for participants to continue to have these assessments. • Following the primary analysis, an additional survival analysis was performed as a consequence of regulatory agency request to provide further mature survival data during their review process.

    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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