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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label, Phase 3 Study of Gemcitabine-Cisplatin Chemotherapy Plus Necitumumab (IMC-11F8) Versus Gemcitabine-Cisplatin Chemotherapy Alone in the First-Line Treatment of Patients With Stage IV Squamous Non-Small Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    		 2009-013838-25
    Trial protocol
    		 BE   AT   DE   HU   PT   ES   GR   SK   IT   GB  
    Global end of trial date
    30 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2025
    First version publication date
    15 Jun 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I4X-IE-JFCC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00981058
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Additional Identifier: IMCLCP11-0806
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Clinical Trial Information, Eli Lilly and Company, 1 08772854559, EU_Lilly_Clinical_Trials@lilly.com
    Scientific contact
    Clinical Trial Information, Eli Lilly and Company, 1 877CTLilly, EU_Lilly_Clinical_Trials@lilly.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
    30 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the overall survival (OS) in patients with Stage IV squamous NSCLC (per the AJCC Staging Manual, Seventh Edition) treated with IMC-11F8 plus gemcitabine-cisplatin chemotherapy (Arm A) versus gemcitabine-cisplatin chemotherapy alone (Arm B) in the first-line metastatic setting.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jan 2010
    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
    Poland: 128
    Country: Number of subjects enrolled
    Portugal: 17
    Country: Number of subjects enrolled
    Romania: 91
    Country: Number of subjects enrolled
    Slovakia: 19
    Country: Number of subjects enrolled
    Spain: 58
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 73
    Country: Number of subjects enrolled
    Germany: 108
    Country: Number of subjects enrolled
    Greece: 32
    Country: Number of subjects enrolled
    Hungary: 84
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Russian Federation: 195
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Thailand: 9
    Country: Number of subjects enrolled
    Brazil: 58
    Country: Number of subjects enrolled
    Korea, Republic of: 47
    Country: Number of subjects enrolled
    Serbia: 24
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Philippines: 20
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Australia: 10
    Worldwide total number of subjects
    1093
    EEA total number of subjects
    657
    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)
    668
    From 65 to 84 years
    424
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Not applicable.

    Pre-assignment
    Screening details
    		 Completers are defined as those participants who died due to any cause in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Necitumumab + Gemcitabine + Cisplatin
    Arm description
    		 Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Necitumumab
    Investigational medicinal product code
    Other name
    LY3012211, IMC-11F8
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    LY2334737
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Arm title
    		 Gemcitabine + Cisplatin
    Arm description
    		 Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    LY2334737
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously.

    Number of subjects in period 1
    		Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Started
    545
    548
    Received at Least 1 Dose of Study Drug
    538
    541
    Completed
    476
    487
    Not completed
    69
    61
         Physician decision
    4
    5
         Consent withdrawn by subject
    24
    22
         Progressive Disease
    38
    31
         Lost to follow-up
    3
    2
         Randomization Error
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Necitumumab + Gemcitabine + Cisplatin
    Reporting group description
    		 Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

    Reporting group title
    Gemcitabine + Cisplatin
    Reporting group description
    		 Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

    Reporting group values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin Total
    Number of subjects
    		 545 548 1093
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 62 (32 to 84) 62 (32 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 95 90 185
        Male
    		 450 458 908
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 55 56 111
        Not Hispanic or Latino
    		 489 490 979
        Unknown or Not Reported
    		 1 2 3
    Race/Ethnicity
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 43 42 85
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 5 6 11
        White
    		 457 456 913
        More than one race
    		 1 0 1
        Other
    		 38 43 81
    Region of Enrollment
    Units: Subjects
        Russian Federation
    		 94 101 195
        Singapore
    		 1 2 3
        United States
    		 20 16 36
        Thailand
    		 3 6 9
        Portugal
    		 8 9 17
        Greece
    		 18 14 32
        Austria
    		 4 4 8
        Brazil
    		 28 30 58
        Republic of Korea
    		 24 23 47
        Poland
    		 69 59 128
        Slovakia
    		 9 10 19
        France
    		 34 39 73
        Serbia
    		 11 13 24
        Croatia
    		 2 4 6
        Romania
    		 46 45 91
        Hungary
    		 43 41 84
        Philippines
    		 12 8 20
        United Kingdom
    		 9 10 19
        Spain
    		 33 25 58
        Canada
    		 2 4 6
        Belgium
    		 4 4 8
        Taiwan
    		 3 2 5
        Italy
    		 13 12 25
        South Africa
    		 2 2 4
        Australia
    		 4 6 10
        Germany
    		 49 59 108

    End points

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    End points reporting groups
    Reporting group title
    Necitumumab + Gemcitabine + Cisplatin
    Reporting group description
    		 Necitumumab + Gemcitabine + Cisplatin Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

    Reporting group title
    Gemcitabine + Cisplatin
    Reporting group description
    		 Gemcitabine + Cisplatin Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

    Primary: Overall Survival Time (OS)

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    End point title
    		 Overall Survival Time (OS)
    End point description
    Overall survival is defined as the time from randomization to death from any cause. Participants who do not die at the end of the extended follow-up period, or were lost to follow-up during the study, were censored at the last date they were known to be alive. OS was estimated by the Kaplan-Meier method. Analysis Population Description (APD): All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 127, Gemcitabine + Cisplatin = 106
    End point type
    Primary
    End point timeframe
    Randomization to Death from Any Cause (Up to 31 Months)
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    545
    548
    Units: Months
        median (confidence interval 95%)
    11.5 (10.4 to 12.6)
    9.9 (8.9 to 11.1)
    Statistical analysis title
    		 Outcome Measure No. 1
    Comparison groups
    Necitumumab + Gemcitabine + Cisplatin v Gemcitabine + Cisplatin
    Number of subjects included in analysis
    1093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.012
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.842
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.736
         upper limit
    		 0.962
    Notes
    [1] - Superiority or Other (legacy)

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the time from randomization until the first radiographic documentation of objective measured progressive disease as defined by RECIST (Version 1.0), or death from any cause. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions. Participants who die without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment. If no baseline or postbaseline radiologic assessment was available, the participants were censored at the date of randomization. If death or PD occurs after two or more consecutive missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits.
    End point type
    Secondary
    End point timeframe
    Randomization to Measured Progressive Disease or Death from Any Cause (Up to 31 Months). APD: All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 114, Gemcitabine + Cisplatin = 131
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    545
    548
    Units: Months
        median (confidence interval 95%)
    5.7 (5.6 to 6.0)
    5.5 (4.8 to 5.6)
    Statistical analysis title
    		 Outcome Measure No. 2
    Comparison groups
    Gemcitabine + Cisplatin v Necitumumab + Gemcitabine + Cisplatin
    Number of subjects included in analysis
    1093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0201
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.851
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.743
         upper limit
    		 0.975
    Notes
    [2] - Superiority or Other (legacy)

    Secondary: Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR])

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    End point title
    		 Percentage of Participants Achieving Complete Response (CR) and Partial Response (PR) (Objective Response Rate [ORR])
    End point description
    ORR is confirmed best overall tumor response of CR or PR. According to RECIST v1.0, CR was defined as the disappearance of all target and non-target lesions. PR defined as a >=30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD; Percentage of participants was calculated as: (total number of participants with CR or PR from start of the treatment until disease progression or recurrence)/total number of participants treated) * 100. APD: All randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Measured Progressive Disease (Up to 31 Months)
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    545
    548
    Units: Percentage of participants
        number (confidence interval 95%)
    31.2 (27.4 to 35.2)
    28.8 (25.2 to 32.8)
    Statistical analysis title
    		 Outcome Measure No. 3
    Comparison groups
    Necitumumab + Gemcitabine + Cisplatin v Gemcitabine + Cisplatin
    Number of subjects included in analysis
    1093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.3997
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.45
    Notes
    [3] - Superiority or Other (legacy)

    Secondary: Mean Change From Baseline in Patient Reported Outcomes (PRO) Using the European Quality of Life-5 Dimension (EQ-5D)

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    End point title
    		 Mean Change From Baseline in Patient Reported Outcomes (PRO) Using the European Quality of Life-5 Dimension (EQ-5D)
    End point description
    The EQ-5D is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three level scale 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). APD: All randomized participants who had evaluable baseline and postbaseline EQ-5D data.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Cycle = 3 Weeks)
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    305
    245
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.0053 ( 0.23626 )
    -0.0083 ( 0.23866 )
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure (TTF)

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    End point title
    		 Time to Treatment Failure (TTF)
    End point description
    TTF is defined as the time from the date of randomization until the date of the first radiographic documentation of PD, death from any cause, discontinuation of treatment for any reason, or initiation of new cancer therapy. Participants who withdrew from the study for reasons other than progression or death were censored at the date of study withdrawal. Participants who did not meet any of the criteria for treatment failure were censored at their date of last contact in the study. APD: All randomized participants. Censored participants: Necitumumab + Gemcitabine + Cisplatin = 16, Gemcitabine + Cisplatin =20
    End point type
    Secondary
    End point timeframe
    Randomization to Measured Progressive Disease, Death From Any Cause, Discontinuation of Treatment or Initiation of New Anticancer Therapy (Up to 31 Months)
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    545
    548
    Units: Months
        median (confidence interval 95%)
    4.3 (4.2 to 4.8)
    3.6 (3.3 to 4.1)
    Statistical analysis title
    		 Outcome Measure No. 5
    Comparison groups
    Necitumumab + Gemcitabine + Cisplatin v Gemcitabine + Cisplatin
    Number of subjects included in analysis
    1093
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0061
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.844
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.747
         upper limit
    		 0.943
    Notes
    [4] - Superiority or Other (legacy)

    Secondary: Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS)

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    End point title
    		 Mean Change From Baseline in PRO Using the Outcomes Lung Cancer Symptom Scale (LCSS)
    End point description
    The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 items were global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-mm lines. A higher score for any item represented a higher level of symptoms/problems. Scores for each of the reported categories ranged from 0 (for best outcome) to 100 (for worst outcome). The Average Symptom Burden Index (ASBI) was the mean of the 6 symptom items of the LCSS, and the Total LCSS was the mean of all 9 LCSS items. ASBI and Total LCSS were not computed for a participant if he/she had 1 or more missing values for the 6 and 9 items, respectively. APD: All randomized participants who had evaluable data for LCSS.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Cycle = 3 Weeks)
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    545
    548
    Units: millimeter (mm)
    arithmetic mean (standard deviation)
        Loss of Appetite (n=304, 242)
    1.8 ( 31.84 )
    1.5 ( 29.30 )
        Fatigue (n=302, 242)
    6.3 ( 29.15 )
    3.5 ( 25.29 )
        Cough (n=303, 243)
    -7.8 ( 28.05 )
    -9.1 ( 25.74 )
        Dyspnea (n=305, 244)
    -2.8 ( 26.52 )
    -1.8 ( 25.27 )
        Pain (n=302, 243)
    -3.3 ( 17.98 )
    -2.2 ( 17.22 )
        Overall Symptoms (n=303, 242)
    -0.3 ( 26.19 )
    -0.6 ( 26.92 )
        Interference (n=306,241)
    3.8 ( 29.74 )
    2.2 ( 26.79 )
        Quality of Life (n=305, 243)
    -0.3 ( 27.35 )
    -1.6 ( 24.71 )
        Average Symptom Burden Index (ASBI) (n=294, 234)
    -1.9 ( 16.55 )
    -1.5 ( 16.52 )
        LCSS Total Score (n=290, 228)
    -0.8 ( 17.03 )
    -0.8 ( 16.17 )
    No statistical analyses for this end point

    Secondary: Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC)

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    End point title
    		 Number of Participants With an Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC)
    End point description
    EGFR IHC Histoscore H-score = weighted sum of % 1+ cells, twice % 2+ cells, and three times % 3+ cells. IHC H-score criteria was used to assess participants with a low EGFR expression defined by a H-score cutoff value of <200 and participants with a high EGFR expression defined by a H-score of cutoff value of >=200. APD: All randomized participants who received at least one dose of study drug and had evaluable data for EGFR IHC.
    End point type
    Secondary
    End point timeframe
    31 Months
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin Gemcitabine + Cisplatin
    Number of subjects analysed
    486
    496
    Units: Participants
        00
    24
    23
        >0
    462
    473
        <200
    295
    313
        >=200
    191
    183
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab

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    End point title
    		 Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab [5]
    End point description
    APD: All randomized participants who received at least one dose of study drug and had evaluable data for PK.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 2, 3, 4, 5 and 6 Prior to Necitumumab Drug Infusion, Up to 24 Months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All randomized participants who received at least one dose of study drug and had evaluable data for PK were included in this analysis. No inferential statistics was planned for this end point.
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    545
    Units: micrograms/milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Predose Cycle 2 Day 1 (n=419)
    52.4 ( 95.9 )
        Predose Cycle3 Day 1 (n=386)
    76.6 ( 80.6 )
        Predose Cycle 4 Day 1 (n=344)
    94.5 ( 92.2 )
        Predose Cycle 5 Day 1 (n=297)
    101 ( 90 )
        Predose Cycle 6 Day 1 (n=262)
    98.5 ( 80 )
    No statistical analyses for this end point

    Secondary: Number of Participants With a Serum Anti-Necitumumab Antibody Assessment

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    End point title
    		 Number of Participants With a Serum Anti-Necitumumab Antibody Assessment [6]
    End point description
    A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were detected at any time point. APD: All randomized participants who received who received at least 1 dose of drug and had evaluable data for antibodies.
    End point type
    Secondary
    End point timeframe
    Baseline through 31 Months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All randomized participants who received who received at least 1 dose of drug and had evaluable data for antibodies were included in this analysis. No inferential statistics was planned for this end point.
    End point values
    		 Necitumumab + Gemcitabine + Cisplatin
    Number of subjects analysed
    528
    Units: Participants
        Participants with at least 1 positive titer
    81
        Neutralizing antibody detected
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline Up To 156 Months
    Adverse event reporting additional description
    All participants who received at least one dose of study drug. The adverse events were analyzed and reported according to the study treatments pre-specified in the statistical analysis plan.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Gemcitabine + Cisplatin
    Reporting group description
    		 Gemcitabine: 1250 mg/m2 on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

    Reporting group title
    Necitumumab + Gemcitabine + Cisplatin
    Reporting group description
    		 Necitumumab: 800 milligrams (mg) I.V. infusion on Days 1 and 8 of every 3 week cycle. Continues until progressive disease, toxicity, noncompliance, or withdrawal. Gemcitabine: 1250 milligrams/square meter (mg/m2) on Days 1 and 8 of every 3 week cycle. Continues for a maximum of six cycles. Cisplatin: 75 mg/m2 IV on Day 1 of every 3 week cycle. Continues for a maximum of six cycles.

    Serious adverse events
    		 Gemcitabine + Cisplatin Necitumumab + Gemcitabine + Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    208 / 541 (38.45%)
    262 / 538 (48.70%)
         number of deaths (all causes)
    487
    476
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    cancer pain
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to bone
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to central nervous system
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    non-small cell lung cancer
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    23 / 541 (4.25%)
    26 / 538 (4.83%)
         occurrences causally related to treatment / all
    0 / 23
    1 / 26
         deaths causally related to treatment / all
    0 / 19
    1 / 24
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypertensive crisis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypovolaemic shock
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    peripheral artery occlusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    orthostatic hypotension
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral venous disease
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral embolism
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral artery thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    superior vena cava syndrome
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    superior vena cava occlusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    superficial vein thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vena cava thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis limb
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chills
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    8 / 538 (1.49%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 3
    1 / 8
    fatigue
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    4 / 541 (0.74%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    7 / 541 (1.29%)
    8 / 538 (1.49%)
         occurrences causally related to treatment / all
    1 / 7
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    generalised oedema
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oedema
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oedema peripheral
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    4 / 541 (0.74%)
    7 / 538 (1.30%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    social stay hospitalisation
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    pelvic pain
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    acute pulmonary oedema
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    bronchitis chronic
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cough
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    4 / 541 (0.74%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epistaxis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    9 / 541 (1.66%)
    11 / 538 (2.04%)
         occurrences causally related to treatment / all
    2 / 9
    4 / 11
         deaths causally related to treatment / all
    0 / 5
    1 / 4
    interstitial lung disease
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    lung infiltration
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary toxicity
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pharyngeal inflammation
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary artery thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    9 / 541 (1.66%)
    19 / 538 (3.53%)
         occurrences causally related to treatment / all
    5 / 9
    14 / 19
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    pulmonary haemorrhage
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    5 / 541 (0.92%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    pulmonary hypertension
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    pulmonary oedema
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary venous thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract haemorrhage
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    abnormal behaviour
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    alcohol abuse
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    completed suicide
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    confusional state
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    delirium
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood creatinine increased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    6 / 538 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood phosphorus decreased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    c-reactive protein increased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ecg signs of myocardial ischaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    false positive investigation result
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoglobin decreased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    platelet count decreased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femoral neck fracture
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    head injury
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    incorrect dose administered
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    medication error
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    21 / 541 (3.88%)
    12 / 538 (2.23%)
         occurrences causally related to treatment / all
    1 / 21
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    overdose
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    toxicity to various agents
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vascular graft occlusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    underdose
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    tracheo-oesophageal fistula
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    acute coronary syndrome
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    acute myocardial infarction
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    4 / 541 (0.74%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial flutter
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac arrest
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    cardiac failure
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    cardiac failure acute
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    cardiac failure congestive
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cardiac tamponade
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardio-respiratory arrest
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    coronary artery disease
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial ischaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    pericarditis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericardial effusion malignant
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericardial effusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    supraventricular tachycardia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ataxia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    brain oedema
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    cerebral haemorrhage
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral infarction
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral ischaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    encephalopathy
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    epilepsy
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hydrocephalus
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hemiplegia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    loss of consciousness
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    paraesthesia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral motor neuropathy
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    presyncope
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radiculopathy
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radial nerve palsy
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sciatica
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal cord compression
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vocal cord paralysis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    agranulocytosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    17 / 541 (3.14%)
    22 / 538 (4.09%)
         occurrences causally related to treatment / all
    15 / 17
    21 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    7 / 541 (1.29%)
    6 / 538 (1.12%)
         occurrences causally related to treatment / all
    7 / 7
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    4 / 541 (0.74%)
    6 / 538 (1.12%)
         occurrences causally related to treatment / all
    4 / 4
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    33 / 541 (6.10%)
    20 / 538 (3.72%)
         occurrences causally related to treatment / all
    31 / 33
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myelosuppression
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancytopenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    6 / 538 (1.12%)
         occurrences causally related to treatment / all
    3 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    thrombocytosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    20 / 541 (3.70%)
    17 / 538 (3.16%)
         occurrences causally related to treatment / all
    20 / 20
    16 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    deafness bilateral
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ototoxicity
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain upper
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colitis ischaemic
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenal ulcer
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenal ulcer perforation
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enteritis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    5 / 541 (0.92%)
    8 / 538 (1.49%)
         occurrences causally related to treatment / all
    3 / 5
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric haemorrhage
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    gastric ulcer
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroduodenal ulcer
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal disorder
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematemesis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematochezia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mesenteric vein thrombosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis acute
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    12 / 538 (2.23%)
         occurrences causally related to treatment / all
    2 / 2
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct stenosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholelithiasis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatorenal syndrome
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    dermatitis acneiform
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dermatitis allergic
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rash maculo-papular
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin fissures
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin toxicity
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin ulcer
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    5 / 541 (0.92%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    4 / 5
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    nephrotic syndrome
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    nephropathy toxic
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    6 / 541 (1.11%)
    8 / 538 (1.49%)
         occurrences causally related to treatment / all
    6 / 6
    7 / 8
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    renal infarct
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal tubular necrosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    5 / 538 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intervertebral disc protrusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteolysis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pathological fracture
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain in extremity
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bacterial infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    6 / 538 (1.12%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cystitis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dental gangrene
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    escherichia urinary tract infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infectious pleural effusion
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    injection site abscess
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    4 / 541 (0.74%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenic sepsis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    oral fungal infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    20 / 541 (3.70%)
    13 / 538 (2.42%)
         occurrences causally related to treatment / all
    6 / 20
    2 / 13
         deaths causally related to treatment / all
    0 / 3
    2 / 6
    pneumonia bacterial
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia necrotising
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyelonephritis acute
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary tuberculosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    septic shock
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    5 / 541 (0.92%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    respiratory tract infection bacterial
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper respiratory tract infection bacterial
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    urinary tract infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urosepsis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    8 / 541 (1.48%)
    5 / 538 (0.93%)
         occurrences causally related to treatment / all
    7 / 8
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diabetic ketoacidosis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    electrolyte imbalance
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypomagnesaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    2 / 538 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperuricaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperkalaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypercreatininaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 538 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    6 / 541 (1.11%)
    4 / 538 (0.74%)
         occurrences causally related to treatment / all
    5 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypophosphataemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 538 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    2 / 541 (0.37%)
    3 / 538 (0.56%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Gemcitabine + Cisplatin Necitumumab + Gemcitabine + Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    512 / 541 (94.64%)
    518 / 538 (96.28%)
    Investigations
    blood creatinine increased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    41 / 541 (7.58%)
    49 / 538 (9.11%)
         occurrences all number
    41
    49
    weight decreased
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    36 / 541 (6.65%)
    73 / 538 (13.57%)
         occurrences all number
    36
    73
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    42 / 541 (7.76%)
    55 / 538 (10.22%)
         occurrences all number
    42
    55
    headache
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    32 / 541 (5.91%)
    57 / 538 (10.59%)
         occurrences all number
    32
    57
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    246 / 541 (45.47%)
    221 / 538 (41.08%)
         occurrences all number
    246
    221
    leukopenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    85 / 541 (15.71%)
    71 / 538 (13.20%)
         occurrences all number
    85
    71
    neutropenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    229 / 541 (42.33%)
    220 / 538 (40.89%)
         occurrences all number
    229
    220
    thrombocytopenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    124 / 541 (22.92%)
    103 / 538 (19.14%)
         occurrences all number
    124
    103
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    112 / 541 (20.70%)
    125 / 538 (23.23%)
         occurrences all number
    112
    125
    fatigue
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    121 / 541 (22.37%)
    117 / 538 (21.75%)
         occurrences all number
    121
    117
    oedema peripheral
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    42 / 541 (7.76%)
    44 / 538 (8.18%)
         occurrences all number
    42
    44
    pyrexia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    61 / 541 (11.28%)
    70 / 538 (13.01%)
         occurrences all number
    61
    70
    Gastrointestinal disorders
    abdominal pain upper
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    29 / 541 (5.36%)
    31 / 538 (5.76%)
         occurrences all number
    29
    31
    constipation
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    101 / 541 (18.67%)
    111 / 538 (20.63%)
         occurrences all number
    101
    111
    diarrhoea
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    60 / 541 (11.09%)
    84 / 538 (15.61%)
         occurrences all number
    60
    84
    dyspepsia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    22 / 541 (4.07%)
    27 / 538 (5.02%)
         occurrences all number
    22
    27
    nausea
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    284 / 541 (52.50%)
    265 / 538 (49.26%)
         occurrences all number
    284
    265
    stomatitis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    32 / 541 (5.91%)
    58 / 538 (10.78%)
         occurrences all number
    32
    58
    vomiting
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    134 / 541 (24.77%)
    153 / 538 (28.44%)
         occurrences all number
    134
    153
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    72 / 541 (13.31%)
    93 / 538 (17.29%)
         occurrences all number
    72
    93
    dyspnoea
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    79 / 541 (14.60%)
    93 / 538 (17.29%)
         occurrences all number
    79
    93
    epistaxis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    16 / 541 (2.96%)
    40 / 538 (7.43%)
         occurrences all number
    16
    40
    haemoptysis
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    22 / 541 (4.07%)
    49 / 538 (9.11%)
         occurrences all number
    22
    49
    productive cough
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    12 / 541 (2.22%)
    29 / 538 (5.39%)
         occurrences all number
    12
    29
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    70 / 541 (12.94%)
    76 / 538 (14.13%)
         occurrences all number
    70
    76
    dermatitis acneiform
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    80 / 538 (14.87%)
         occurrences all number
    3
    80
    dry skin
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    8 / 541 (1.48%)
    35 / 538 (6.51%)
         occurrences all number
    8
    35
    acne
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    3 / 541 (0.55%)
    47 / 538 (8.74%)
         occurrences all number
    3
    47
    pruritus
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    5 / 541 (0.92%)
    39 / 538 (7.25%)
         occurrences all number
    5
    39
    rash
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    32 / 541 (5.91%)
    252 / 538 (46.84%)
         occurrences all number
    32
    252
    skin fissures
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    0 / 541 (0.00%)
    27 / 538 (5.02%)
         occurrences all number
    0
    27
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    30 / 541 (5.55%)
    29 / 538 (5.39%)
         occurrences all number
    30
    29
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    31 / 541 (5.73%)
    31 / 538 (5.76%)
         occurrences all number
    31
    31
    back pain
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    30 / 541 (5.55%)
    38 / 538 (7.06%)
         occurrences all number
    30
    38
    pain in extremity
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    21 / 541 (3.88%)
    27 / 538 (5.02%)
         occurrences all number
    21
    27
    Infections and infestations
    paronychia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    1 / 541 (0.18%)
    36 / 538 (6.69%)
         occurrences all number
    1
    36
    urinary tract infection
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    13 / 541 (2.40%)
    31 / 538 (5.76%)
         occurrences all number
    13
    31
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    153 / 541 (28.28%)
    162 / 538 (30.11%)
         occurrences all number
    153
    162
    hyperglycaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    16 / 541 (2.96%)
    28 / 538 (5.20%)
         occurrences all number
    16
    28
    hyperkalaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    19 / 541 (3.51%)
    27 / 538 (5.02%)
         occurrences all number
    19
    27
    hypokalaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    27 / 541 (4.99%)
    37 / 538 (6.88%)
         occurrences all number
    27
    37
    hypomagnesaemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    82 / 541 (15.16%)
    159 / 538 (29.55%)
         occurrences all number
    82
    159
    hyponatraemia
    alternative dictionary used: MedDRA 27.1
         subjects affected / exposed
    29 / 541 (5.36%)
    23 / 538 (4.28%)
         occurrences all number
    29
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2010
    - Updated secondary and exploratory objectives to reflect modification in the biomarker program; - Updated inclusion criteria for more clarity; - Updated efficacy and pharmacokinetic assessment data to reflect change in medical processes.
    09 Jun 2011
    -Serious adverse events reporting information was updated; - Thromboembolic events section was added;
    28 May 2013
    - A secondary objective was deleted, and some exploratory objectives were amended to reflect prioritization of biomarker analyses on current scientific data. - Changes made to tumor tissue collection and blood sampling collection to be consistent with changes made to objectives.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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