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    Clinical Trial Results:
    VIP: A prospective, phase II, double blinded, multicentre, randomised clinical trial comparing combination gemcitabine and vandetanib therapy with gemcitabine therapy alone in locally advanced or metastatic pancreatic carcinoma.

    Summary
    EudraCT number
    		 2010-021951-26
    Trial protocol
    		 GB  
    Global end of trial date
    05 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UoL000621/R&D3963
    Additional study identifiers
    ISRCTN number
    		 ISRCTN74555382
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    765 Brownlow Hill, Liverpool, United Kingdom, L69 7ZX
    Public contact
    Charlotte Rawcliffe, Liverpool Clinical Trials Centre, +44 01517948167, clr001@liverpool.ac.uk
    Scientific contact
    Charlotte Rawcliffe, Liverpool Clinical Trials Centre, +44 01517948167, clr001@liverpool.ac.uk
    Sponsor organisation name
    The Royal Liverpool and Broadgreen Hospitals NHS Trust
    Sponsor organisation address
    Prescot Street, Liverpool, United Kingdom, L7 8XP
    Public contact
    Heather Rogers, The Royal Liverpool and Broadgreen Hospitals NHS Trust, +44 0151 706 3321, Heather.Rogers@rlbuht.nhs.uk
    Scientific contact
    Heather Rogers, The Royal Liverpool and Broadgreen Hospitals NHS Trust, +44 0151 706 3321, Heather.Rogers@rlbuht.nhs.uk
    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
    07 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether overall survival time using gemcitabine plus vandetanib is longer than that using gemcitabine alone as the first treatment for advanced or metastatic pancreatic cancer.
    Protection of trial subjects
    Central and on-site monitoring was conducted to help protect patients and to monitor performance relating to trial procedures, trial intervention, administration and laboratory/data collection processes. A risk assessment was carried out to determine the level of monitoring required and subsequently a monitoring plan was developed to document how and when monitoring is conducted and to what extent. Patient safety data was monitored via LCTU pharmacovigilance procedures (reporting and review of adverse event data) and by an ISDMC. A Trial Management Group regularly reviewed central monitoring reports and advised accordingly. Serious adverse events were followed up until resolution or death. Annual safety reports were submitted to the national regulatory authorities.
    Background therapy
    		 -
    Evidence for comparator
    		 For patients with locally advanced or metastatic pancreatic carcinoma who wish to have and are fit enough to benefit from active treatment, chemotherapy with single agent gemcitabine has for several years been the standard of care. The only trial to demonstrate an incremental improvement in efficacy for the addition of another drug to the gemcitabine/erlotinib combination is AVITA (conducted in patients with metastatic disease alone). Although this trial failed to reach its primary end point of improved OS with the addition of bevacizumab, PFS was significantly prolonged and there was a strong trend for improved response rate. Thus, there is a strong clinical evidence-based rationale for building upon and further investigating the impact of dual EGFR and VEGFR blockade in pancreatic cancer. Vandetanib inhibits a third tyrosine kinase and this may significantly augment the therapeutic impact of dual VEGRF/EGFR inhibition in pancreatic cancer. In this trial vandetanib is combined with gemcitabine and outcome compared with gemcitabine alone, given that gemcitabine monotherapy remains a regulatory standard of care and a globally accepted trial comparator. After discussion with Vandetanib team at Astra Zeneca an initial dose of 300mg/day of vandetanib in combination with gemcitabine was selected for use in the VIP study. Therefore half of the patients on the study were treated with an oral placebo alongside gemcitabine and the other half received vandetanib alongside gemcitabine.
    Actual start date of recruitment
    01 Sep 2011
    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
    United Kingdom: 142
    Worldwide total number of subjects
    142
    EEA total number of subjects
    142
    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)
    60
    From 65 to 84 years
    82
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 UK only. The ViP study recruited 142 patients across 18 centres across England and Northern Ireland between 24 October 2011 and 09 October 2013. First patient, first visit (FPFV; date of randomisation): 24 October 2011. Follow up data included up to 15 July 2015.

    Pre-assignment
    Screening details
    		 142 of the 382 patients screened were recruited to the study. Screening: Informed consent; Histology/Cytology; Demography & medical history; Concomitant medication; Physical examination & medical review; ECOG; 12-lead ECG; CT scan chest, abdomen & pelvis; Haematological/Clinical Chemistry; Vital signs; Translational bloods; CA19-9; pregnancy test.

    Period 1
    Period 1 title
    Treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    VIP is designed as a double blinded trial with clinicians and all members of the trial management team being blind to which treatment a patient is randomised to. Members of the DMC shall be un-blind to enable them to assess the performance of the trial. The VIP Trial Statistician is partially un-blind and will receive a 0/1 indicator to differentiate between the two treatments (without being made aware of what 0/1 represent) so they can produce reports.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Placebo plus Gemcitabine
    Arm description
    		 Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles
    Arm type
    		 Placebo plus IMP

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Gemzar
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000mg/m2 must be given as an intravenous infusion over 30 minutes unless haematological toxicity occurs requiring dose adjustment.

    Arm title
    		 Arm B: Vandetanib plus Gemcitabine
    Arm description
    		 Vandetanib orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    Other name
    ZD6474
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once a day continuously.

    Number of subjects in period 1
    		Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Started
    70
    72
    Completed
    69
    68
    Not completed
    1
    4
         Symptomatic deterioration
    -
    1
         Patient became ill for treatment at randomisation
    1
    1
         Patient stopped treatment
    -
    1
         Clinical deterioration
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Placebo plus Gemcitabine
    Reporting group description
    		 Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles

    Reporting group title
    Arm B: Vandetanib plus Gemcitabine
    Reporting group description
    		 Vandetanib orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

    Reporting group values
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine Total
    Number of subjects
    		 70 72 142
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 67.5 (61 to 73) 66.5 (61 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 40 43 83
        Male
    		 30 29 59
    Ethnicity
    Units: Subjects
        White
    		 60 67 127
        Asian
    		 4 3 7
        Black
    		 3 0 3
        Other
    		 3 2 5
    Tumour Histology
    Units: Subjects
        Pancreatic ductal adenocarcinoma
    		 62 66 128
        Undiff. carcinoma of the pancreas
    		 8 6 14
    Tumour Site
    Units: Subjects
        Body
    		 13 24 37
        Head
    		 47 31 78
        Tail
    		 5 13 18
        Uncinate
    		 5 4 9
    Tumour Differentiation
    Units: Subjects
        Well
    		 7 6 13
        Moderate
    		 12 16 28
        Poor
    		 14 12 26
        Undifferentiated
    		 1 4 5
        Unknown
    		 29 30 59
        Cannot be assessed
    		 7 4 11
    Smoking status
    Units: Subjects
        Current Smoker
    		 10 19 29
        Ex smoker
    		 23 30 53
        Never Smoked
    		 34 20 54
        Not recorded
    		 3 3 6
    ECG
    Units: IQR
        median (inter-quartile range (Q1-Q3))
    		 426 (408.25 to 436.75) 418.5 (399 to 435.75) -
    Haemoglobin
    Units: g/dl
        median (inter-quartile range (Q1-Q3))
    		 12.93 (11.9 to 13.575) 12.7 (11.775 to 13.525) -
    WBC
    Units: 10/L
        median (inter-quartile range (Q1-Q3))
    		 7.67 (6.275 to 10.475) 7.88 (6.777 to 9.65) -
    Neutrophils
    Units: 10*9/L
        median (inter-quartile range (Q1-Q3))
    		 4.95 (4.047 to 6.65) 5.185 (4.3 to 6.85) -
    Lymphocytes
    Units: 10*9/L
        median (inter-quartile range (Q1-Q3))
    		 1.6 (1.2 to 2.055) 1.4 (1.1 to 2.145) -
    Platelets
    Units: 10*9/L
        median (inter-quartile range (Q1-Q3))
    		 240.5 (198 to 297) 246.5 (200.5 to 315.5) -
    Albumin
    Units: g/L
        median (inter-quartile range (Q1-Q3))
    		 40 (37 to 44.75) 40 (37 to 43) -
    Blood Urea
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 4.65 (3.825 to 6.175) 4.35 (3.7 to 5.6) -
    Bilirubin
    Units: ymol/L
        median (inter-quartile range (Q1-Q3))
    		 8 (6 to 12.75) 8 (6.75 to 12) -
    Potassium
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 4.4 (4.2 to 4.6) 4.5 (4.3 to 4.7) -
    Corr'c Calcium
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 2.385 (2.33 to 2.46) 2.355 (2.28 to 2.422) -
    Serum Creatinine
    Units: umol/L
        median (inter-quartile range (Q1-Q3))
    		 71.5 (61.25 to 80) 65 (58.5 to 73.25) -
    Sodium
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 138 (136 to 140) 138 (135 to 140) -
    y-GT
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 86 (43 to 251) 69 (35.75 to 158.25) -
    CA19-9
    Units: KU/L
        median (inter-quartile range (Q1-Q3))
    		 1259.5 (264.75 to 6080.25) 1018 (199 to 6104) -
    ALT
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 28.5 (22.25 to 39.5) 23.5 (16 to 40) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Placebo plus Gemcitabine
    Reporting group description
    		 Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles

    Reporting group title
    Arm B: Vandetanib plus Gemcitabine
    Reporting group description
    		 Vandetanib orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Participants were assessed whether overall survival time using gemcitabine plus vandetanib is longer than that using gemcitabine alone as first line treatment for advanced pancreatic cancer.
    End point type
    Primary
    End point timeframe
    Time is measured from randomisation to death from any cause.
    End point values
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Number of subjects analysed
    70
    72
    Units: months
        median (confidence interval 95%)
    8.95 (6.55 to 11.74)
    8.83 (7.11 to 11.58)
    Statistical analysis title
    		 OS - Cox Model
    Statistical analysis description
    A stratified Cox regression with 6 strata defined by Stage of disease (locally advanced vs. metastatic) and ECOG Performance status (0 versus 1 versus 2) at baseline.
    Comparison groups
    Arm A: Placebo plus Gemcitabine v Arm B: Vandetanib plus Gemcitabine
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.301
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.53

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Comparison between the two treatment arms for progression-free survival.
    End point type
    Secondary
    End point timeframe
    From randomisation until progression or death from any cause.
    End point values
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Number of subjects analysed
    70
    72
    Units: months
        median (confidence interval 95%)
    6.09 (5 to 9.9)
    8.04 (4.54 to 10.3)
    No statistical analyses for this end point

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Comparison between the two treatment arms for overall response rate.
    End point type
    Secondary
    End point timeframe
    From randomisation until death by any cause.
    End point values
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Number of subjects analysed
    38
    40
    Units: subjects
    9
    10
    No statistical analyses for this end point

    Secondary: Disease control rate

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    End point title
    		 Disease control rate
    End point description
    Comparison between the two treatment arms for disease control, assessed by CT scans per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From randomisation until death from any cause.
    End point values
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Number of subjects analysed
    37
    42
    Units: subjects
    10
    8
    No statistical analyses for this end point

    Secondary: Patient pain assessment

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    End point title
    		 Patient pain assessment
    End point description
    Comparison between the two treatment arms for patient pain assessment.
    End point type
    Secondary
    End point timeframe
    From randomisation until death from any cause.
    End point values
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Number of subjects analysed
    70
    72
    Units: Patients
    median (confidence interval 95%)
        Day 1
    30 (9.5 to 50)
    30 (5 to 50)
        3 Month
    5.5 (0 to 30)
    5 (0 to 30)
        6 Month
    10 (0 to 29)
    1.5 (0 to 35)
        12 Month
    16 (4 to 18.5)
    15 (4.25 to 20.25)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reporting period is patient on study and up to 30 days post last dose of trial treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Arm A: Placebo plus Gemcitabine
    Reporting group description
    		 Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

    Reporting group title
    Arm B: Vandetanib plus Gemcitabine
    Reporting group description
    		 Vandetanib orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

    Serious adverse events
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 70 (60.00%)
    50 / 72 (69.44%)
         number of deaths (all causes)
    61
    70
         number of deaths resulting from adverse events
    6
    7
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    6 / 70 (8.57%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    4 / 70 (5.71%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema limbs
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 70 (5.71%)
    6 / 72 (8.33%)
         occurrences causally related to treatment / all
    4 / 5
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Fever
         subjects affected / exposed
    17 / 70 (24.29%)
    18 / 72 (25.00%)
         occurrences causally related to treatment / all
    18 / 30
    10 / 28
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Flu like symptoms
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pain
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    2 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnea
         subjects affected / exposed
    8 / 70 (11.43%)
    14 / 72 (19.44%)
         occurrences causally related to treatment / all
    3 / 8
    12 / 19
         deaths causally related to treatment / all
    0 / 2
    2 / 3
    Pleuritic pain
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders - Other
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Creatinine increased
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ECG QT corrected interval prolonged
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INR increased
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations - Other, specify
         subjects affected / exposed
    0 / 70 (0.00%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutrophil count decreased
         subjects affected / exposed
    5 / 70 (7.14%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Chest pain - cardiac
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (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
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemia cerebrovascular
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 70 (0.00%)
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Movements involuntary
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stroke
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Syncope
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders - Other, specify
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (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
    Anemia
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    10 / 70 (14.29%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    6 / 12
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Ascites
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    3 / 70 (4.29%)
    9 / 72 (12.50%)
         occurrences causally related to treatment / all
    3 / 4
    7 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    11 / 70 (15.71%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    9 / 15
    2 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Vomiting
         subjects affected / exposed
    16 / 70 (22.86%)
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    12 / 23
    2 / 7
         deaths causally related to treatment / all
    1 / 3
    0 / 3
    Mucositis oral
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bloating
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bile duct stenosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (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
    Erythema multiforme
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders - Other
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin ulceration
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders - Other, specify
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary frequency
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine discoloration
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute kidney injury
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chest wall pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle weakness lower limb
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Gum infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 70 (4.29%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Arm A: Placebo plus Gemcitabine Arm B: Vandetanib plus Gemcitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 70 (91.43%)
    66 / 72 (91.67%)
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    HEMATOMA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    HOT FLASHES
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    2
    HYPERTENSION
         subjects affected / exposed
    11 / 70 (15.71%)
    12 / 72 (16.67%)
         occurrences all number
    77
    103
    HYPOTENSION
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 72 (6.94%)
         occurrences all number
    15
    8
    PERIPHERAL ISCHEMIA
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    PHLEBITIS
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    2
    1
    SUPERFICIAL THROMBOPHLEBITIS
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    THROMBOEMBOLIC EVENT
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 72 (5.56%)
         occurrences all number
    3
    6
    VASCULAR DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    4 / 70 (5.71%)
    8 / 72 (11.11%)
         occurrences all number
    5
    13
    EDEMA FACE
         subjects affected / exposed
    1 / 70 (1.43%)
    4 / 72 (5.56%)
         occurrences all number
    1
    4
    EDEMA LIMBS
         subjects affected / exposed
    9 / 70 (12.86%)
    10 / 72 (13.89%)
         occurrences all number
    28
    42
    EDEMA TRUNK
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    FATIGUE
         subjects affected / exposed
    59 / 70 (84.29%)
    66 / 72 (91.67%)
         occurrences all number
    603
    628
    FEVER
         subjects affected / exposed
    7 / 70 (10.00%)
    8 / 72 (11.11%)
         occurrences all number
    13
    14
    FLU LIKE SYMPTOMS
         subjects affected / exposed
    6 / 70 (8.57%)
    5 / 72 (6.94%)
         occurrences all number
    8
    7
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    2
    4
    HYPOTHERMIA
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    LOCALIZED EDEMA
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    2
    1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    PAIN
         subjects affected / exposed
    5 / 70 (7.14%)
    7 / 72 (9.72%)
         occurrences all number
    11
    31
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    PENILE PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    PROSTATIC PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    VAGINAL DISCHARGE
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    VAGINAL DRYNESS
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    VAGINAL HEMORRHAGE
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    ASPIRATION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    COUGH
         subjects affected / exposed
    6 / 70 (8.57%)
    8 / 72 (11.11%)
         occurrences all number
    12
    14
    DYSPNEA
         subjects affected / exposed
    9 / 70 (12.86%)
    10 / 72 (13.89%)
         occurrences all number
    40
    27
    EPISTAXIS
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 72 (6.94%)
         occurrences all number
    4
    5
    HICCUPS
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    HOARSENESS
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    2
    1
    HYPOXIA
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    LARYNGEAL INFLAMMATION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PLEURITIC PAIN
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    6
    PNEUMONITIS
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    3
    POSTNASAL DRIP
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    2
    PULMONARY EDEMA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    2
    SINUS DISORDER
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    SORE THROAT
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 72 (2.78%)
         occurrences all number
    6
    3
    VOICE ALTERATION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    WHEEZING
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    AGITATION
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    ANXIETY
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 72 (6.94%)
         occurrences all number
    5
    6
    CONFUSION
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    2
    DEPRESSION
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 72 (8.33%)
         occurrences all number
    3
    13
    HALLUCINATIONS
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 72 (0.00%)
         occurrences all number
    7
    0
    INSOMNIA
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 72 (8.33%)
         occurrences all number
    9
    10
    LIBIDO DECREASED
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    3
    PSYCHIATRIC DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    52 / 70 (74.29%)
    63 / 72 (87.50%)
         occurrences all number
    333
    357
    ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    47 / 70 (67.14%)
    61 / 72 (84.72%)
         occurrences all number
    300
    471
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    44 / 70 (62.86%)
    54 / 72 (75.00%)
         occurrences all number
    240
    254
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    15 / 70 (21.43%)
    14 / 72 (19.44%)
         occurrences all number
    34
    22
    CREATININE INCREASED
         subjects affected / exposed
    12 / 70 (17.14%)
    24 / 72 (33.33%)
         occurrences all number
    60
    142
    ELECTROCARDIOGRAM QT CORRECTED INTERVAL PROLONGED
         subjects affected / exposed
    2 / 70 (2.86%)
    23 / 72 (31.94%)
         occurrences all number
    2
    48
    GGT INCREASED
         subjects affected / exposed
    53 / 70 (75.71%)
    59 / 72 (81.94%)
         occurrences all number
    567
    587
    INVESTIGATIONS - OTHER, SPECIFY
         subjects affected / exposed
    45 / 70 (64.29%)
    46 / 72 (63.89%)
         occurrences all number
    330
    353
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    35 / 70 (50.00%)
    40 / 72 (55.56%)
         occurrences all number
    321
    164
    LYMPHOCYTE COUNT INCREASED
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    2
    3
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    42 / 70 (60.00%)
    51 / 72 (70.83%)
         occurrences all number
    259
    273
    PANCREATIC ENZYMES DECREASED
         subjects affected / exposed
    3 / 70 (4.29%)
    1 / 72 (1.39%)
         occurrences all number
    4
    1
    PLATELET COUNT DECREASED
         subjects affected / exposed
    47 / 70 (67.14%)
    62 / 72 (86.11%)
         occurrences all number
    212
    307
    WEIGHT LOSS
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 72 (2.78%)
         occurrences all number
    4
    4
    WHITE BLOOD CELL DECREASED
         subjects affected / exposed
    38 / 70 (54.29%)
    50 / 72 (69.44%)
         occurrences all number
    307
    225
    Injury, poisoning and procedural complications
    BRUISING
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences all number
    3
    2
    FALL
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    3
    WOUND COMPLICATION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    CARDIAC DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    4 / 70 (5.71%)
    3 / 72 (4.17%)
         occurrences all number
    9
    10
    CHEST PAIN - CARDIAC
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    PALPITATIONS
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    3
    SINUS BRADYCARDIA
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    4
    SINUS TACHYCARDIA
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences all number
    3
    6
    Nervous system disorders
    COGNITIVE DISTURBANCE
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    DIZZINESS
         subjects affected / exposed
    5 / 70 (7.14%)
    7 / 72 (9.72%)
         occurrences all number
    23
    14
    DYSGEUSIA
         subjects affected / exposed
    3 / 70 (4.29%)
    8 / 72 (11.11%)
         occurrences all number
    6
    14
    ENCEPHALOPATHY
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    FACIAL MUSCLE WEAKNESS
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    HEADACHE
         subjects affected / exposed
    5 / 70 (7.14%)
    5 / 72 (6.94%)
         occurrences all number
    14
    14
    LETHARGY
         subjects affected / exposed
    42 / 70 (60.00%)
    55 / 72 (76.39%)
         occurrences all number
    288
    323
    MOVEMENTS INVOLUNTARY
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    NEURALGIA
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    PARESTHESIA
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    1 / 70 (1.43%)
    4 / 72 (5.56%)
         occurrences all number
    1
    5
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 72 (4.17%)
         occurrences all number
    1
    5
    SOMNOLENCE
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    SYNCOPE
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    2
    2
    TREMOR
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    2
    6
    VASOVAGAL REACTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    ANEMIA
         subjects affected / exposed
    64 / 70 (91.43%)
    63 / 72 (87.50%)
         occurrences all number
    758
    636
    BLOOD AND LYMPHATIC SYSTEM DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    7
    HEMOLYTIC UREMIC SYNDROME
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    LEUKOCYTOSIS
         subjects affected / exposed
    11 / 70 (15.71%)
    15 / 72 (20.83%)
         occurrences all number
    24
    46
    THROMBOTIC THROMBOCYTOPENIC PURPURA
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    EAR AND LABYRINTH DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    2
    TINNITUS
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    2
    1
    VERTIGO
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    BLURRED VISION
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    4
    EYE DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences all number
    3
    2
    ABDOMINAL PAIN
         subjects affected / exposed
    56 / 70 (80.00%)
    64 / 72 (88.89%)
         occurrences all number
    315
    348
    ANAL PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    ASCITES
         subjects affected / exposed
    4 / 70 (5.71%)
    3 / 72 (4.17%)
         occurrences all number
    4
    9
    BLOATING
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 72 (6.94%)
         occurrences all number
    4
    7
    COLITIS
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    CONSTIPATION
         subjects affected / exposed
    32 / 70 (45.71%)
    40 / 72 (55.56%)
         occurrences all number
    121
    133
    DENTAL CARIES
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    DIARRHEA
         subjects affected / exposed
    34 / 70 (48.57%)
    54 / 72 (75.00%)
         occurrences all number
    176
    373
    DRY MOUTH
         subjects affected / exposed
    4 / 70 (5.71%)
    9 / 72 (12.50%)
         occurrences all number
    6
    13
    DYSPEPSIA
         subjects affected / exposed
    3 / 70 (4.29%)
    3 / 72 (4.17%)
         occurrences all number
    3
    5
    DYSPHAGIA
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    FLATULENCE
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 72 (5.56%)
         occurrences all number
    3
    4
    GASTRITIS
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    GASTROESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences all number
    4
    2
    GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 72 (6.94%)
         occurrences all number
    7
    6
    GASTROINTESTINAL PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    HEMORRHOIDS
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    LIP PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    MALABSORPTION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    MUCOSITIS ORAL
         subjects affected / exposed
    27 / 70 (38.57%)
    23 / 72 (31.94%)
         occurrences all number
    55
    55
    NAUSEA
         subjects affected / exposed
    49 / 70 (70.00%)
    53 / 72 (73.61%)
         occurrences all number
    301
    243
    OBSTRUCTION GASTRIC
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    ORAL PAIN
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    PERIODONTAL DISEASE
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    RECTAL HEMORRHAGE
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    2
    TOOTHACHE
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    VOMITING
         subjects affected / exposed
    39 / 70 (55.71%)
    33 / 72 (45.83%)
         occurrences all number
    112
    72
    Hepatobiliary disorders
    BILE DUCT STENOSIS
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    5 / 70 (7.14%)
    5 / 72 (6.94%)
         occurrences all number
    6
    7
    DRY SKIN
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 72 (6.94%)
         occurrences all number
    4
    9
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    1 / 70 (1.43%)
    3 / 72 (4.17%)
         occurrences all number
    1
    3
    ERYTHRODERMA
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    2
    HYPERHIDROSIS
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 72 (0.00%)
         occurrences all number
    3
    0
    PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    3
    PHOTOSENSITIVITY
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    PRURITUS
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    3
    3
    PURPURA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    RASH ACNEIFORM
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    2
    RASH GENERALIZED
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    2
    2
    RASH MACULO-PAPULAR
         subjects affected / exposed
    20 / 70 (28.57%)
    48 / 72 (66.67%)
         occurrences all number
    87
    249
    SCALP PAIN
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    8 / 70 (11.43%)
    4 / 72 (5.56%)
         occurrences all number
    17
    12
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    SKIN HYPOPIGMENTATION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    SKIN ULCERATION
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    SURGICAL AND MEDICAL PROCEDURES - OTHER
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    9 / 70 (12.86%)
    20 / 72 (27.78%)
         occurrences all number
    25
    72
    HEMATURIA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    2
    PROTEINURIA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    RENAL AND URINARY DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    2 / 70 (2.86%)
    2 / 72 (2.78%)
         occurrences all number
    2
    2
    URINARY FREQUENCY
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 72 (0.00%)
         occurrences all number
    3
    0
    URINARY INCONTINENCE
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    URINARY URGENCY
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    URINE DISCOLORATION
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    ARTHRITIS
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    BACK PAIN
         subjects affected / exposed
    9 / 70 (12.86%)
    9 / 72 (12.50%)
         occurrences all number
    14
    19
    CHEST WALL PAIN
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    5
    3
    FLANK PAIN
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    GENERALIZED MUSCLE WEAKNESS
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    1
    3
    JOINT RANGE OF MOTION DECREASED
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    MUSCLE WEAKNESS LEFT-SIDED
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    MUSCLE WEAKNESS LOWER LIMB
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    MUSCLE WEAKNESS TRUNK
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    MUSCLE WEAKNESS UPPER LIMB
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    2
    3
    MYALGIA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    NECK PAIN
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 72 (2.78%)
         occurrences all number
    5
    6
    Infections and infestations
    BILIARY TRACT INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    BLADDER INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    BRONCHIAL INFECTION
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 72 (2.78%)
         occurrences all number
    8
    2
    CORNEAL INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    GUM INFECTION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
         subjects affected / exposed
    3 / 70 (4.29%)
    8 / 72 (11.11%)
         occurrences all number
    9
    16
    LARYNGITIS
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    LIP INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    LUNG INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    MEDIASTINAL INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    PAPULOPUSTULAR RASH
         subjects affected / exposed
    9 / 70 (12.86%)
    22 / 72 (30.56%)
         occurrences all number
    30
    82
    PENILE INFECTION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    SKIN INFECTION
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    2
    2
    TOOTH INFECTION
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    UPPER RESPIRATORY INFECTION
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 72 (2.78%)
         occurrences all number
    3
    3
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 72 (5.56%)
         occurrences all number
    10
    5
    VAGINAL INFECTION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    WOUND INFECTION
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    ACIDOSIS
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    ANOREXIA
         subjects affected / exposed
    50 / 70 (71.43%)
    59 / 72 (81.94%)
         occurrences all number
    202
    241
    DEHYDRATION
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    HYPERGLYCEMIA
         subjects affected / exposed
    4 / 70 (5.71%)
    3 / 72 (4.17%)
         occurrences all number
    5
    5
    HYPERKALEMIA
         subjects affected / exposed
    10 / 70 (14.29%)
    12 / 72 (16.67%)
         occurrences all number
    18
    20
    HYPERMAGNESEMIA
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 72 (8.33%)
         occurrences all number
    5
    6
    HYPERNATREMIA
         subjects affected / exposed
    0 / 70 (0.00%)
    4 / 72 (5.56%)
         occurrences all number
    0
    11
    HYPOALBUMINEMIA
         subjects affected / exposed
    37 / 70 (52.86%)
    49 / 72 (68.06%)
         occurrences all number
    228
    275
    HYPOCALCEMIA
         subjects affected / exposed
    20 / 70 (28.57%)
    42 / 72 (58.33%)
         occurrences all number
    51
    153
    HYPOGLYCEMIA
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    2
    HYPOKALEMIA
         subjects affected / exposed
    12 / 70 (17.14%)
    15 / 72 (20.83%)
         occurrences all number
    23
    28
    HYPOMAGNESEMIA
         subjects affected / exposed
    11 / 70 (15.71%)
    26 / 72 (36.11%)
         occurrences all number
    56
    83
    HYPONATREMIA
         subjects affected / exposed
    24 / 70 (34.29%)
    35 / 72 (48.61%)
         occurrences all number
    93
    140
    HYPOPHOSPHATEMIA
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    METABOLISM AND NUTRITION DISORDERS - OTHER, SPECIFY
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2012
    Protocol Version 5 (13/DEC/2012). Concomitant Medications/Treatments: Updated to include new guidance from version 14 of the Investigator Brochure describing interactions between vandetanib and metformin, as well as vandetanib and digoxin. Visit Schedule: The visit schedule was updated to stipulate that the medical review and physical examination completed for screening can be used for baseline if within 3 days of day 1 (start of treatment). Appendix C: Tables listing drugs considered to be associated with causing torsades de pointes (Tdp) were updated to reflect the list of drugs on the Arizona CERT website. A statement was also added that investigators need to periodically check the website for the most up to date drugs linked to causing Tdp. Additional information was added to table A (drugs with a high risk of causing Tdp) to clarify that none of the drugs listed in this table are to be taken 2 weeks prior to randomisation or during study treatment. Advice in table B and C was also updated with information on additional ECG and electrolyte monitoring that should be conducted if patients are taking drugs listed whilst on study treatment.
    13 Dec 2013
    Protocol version 6 (26/APR/2013). Main changes from version 5: Date: 13/Dec/2013 The sample size number has been updated throughout the protocol to reflect the additional 20 patients to be recruited, bringing the total to 140. The statistical section has also been updated explaining the reason for the additional patients being added is due to the importance of collecting quality translational samples for the development of a companion diagnostic test. This amendment will be implemented at research sites once regulatory approvals have been received.

    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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