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

    Summary
    EudraCT number
    		 2009-012574-12
    Trial protocol
    		 AT   BE   HU   PT   DE   ES   GR   SK   IT   FR   GB  
    Global end of trial date
    23 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2021
    First version publication date
    28 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I4X-IE-JFCB
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00982111
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 13908
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    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
    23 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The research study is testing the investigational drug necitumumab in the treatment of advanced non-small cell lung cancer. The aim of this study is to determine if necitumumab, given together with a standard chemotherapy combination consisting of cisplatin and pemetrexed will be more effective in improving participant disease than the standard chemotherapy combination alone.
    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
    02 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    Romania: 52
    Country: Number of subjects enrolled
    Hungary: 45
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 67
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Brazil: 72
    Country: Number of subjects enrolled
    Poland: 52
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 159
    Country: Number of subjects enrolled
    Croatia: 2
    Worldwide total number of subjects
    633
    EEA total number of subjects
    485
    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)
    416
    From 65 to 84 years
    216
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Available

    Pre-assignment
    Screening details
    		 Completers included participants who died from any cause and participants who were alive and on study at conclusion however were off treatment.

    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 + Pemetrexed + Cisplatin
    Arm description
    		 Necitumumab + Pemetrexed + Cisplatin Necitumumab: 800 milligrams (mg) (absolute dose) on Days 1 and 8 of every 3-week cycle. Pemetrexed: 500 mg/square meter (mg/m2) intravenous (I.V.) on Day 1 of every 3-week cycle, for a maximum of six cycles. Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Alimta®,LY231514
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 milligram per square meter (mg/m2) administered Intravenously (I.V.) on Day 1 of every 3-week cycle, for a maximum of six cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2 administered I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles

    Investigational medicinal product name
    Necitumumab
    Investigational medicinal product code
    Other name
    IMC-11F8,LY3012211,Portrazza®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg (absolute dose) on Days 1 and 8 of every 3-week cycle, administered as an I.V.

    Arm title
    		 Pemetrexed + Cisplatin
    Arm description
    		 Pemetrexed + Cisplatin Pemetrexed: 500 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles. Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Alimta®,LY231514
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 milligram per square meter (mg/m2) administered Intravenously (I.V.) on Day 1 of every 3-week cycle, for a maximum of six cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2 administered I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles

    Number of subjects in period 1
    		Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Started
    315
    318
    Received at least 1 dose of study drug
    304
    312
    Death Due to Any Cause
    236
    246
    Completed
    236
    246
    Not completed
    79
    72
         Consent withdrawn by subject
    17
    19
         Sponsor's Decision
    -
    1
         Adverse event, non-fatal
    1
    1
         New Anti-Cancer Therapy
    5
    5
         Progressive Disease
    46
    39
         Global Study End
    -
    1
         Medical Decision
    1
    -
         Lost to follow-up
    9
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Necitumumab + Pemetrexed + Cisplatin
    Reporting group description
    		 Necitumumab + Pemetrexed + Cisplatin Necitumumab: 800 milligrams (mg) (absolute dose) on Days 1 and 8 of every 3-week cycle. Pemetrexed: 500 mg/square meter (mg/m2) intravenous (I.V.) on Day 1 of every 3-week cycle, for a maximum of six cycles. Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles.

    Reporting group title
    Pemetrexed + Cisplatin
    Reporting group description
    		 Pemetrexed + Cisplatin Pemetrexed: 500 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles. Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles.

    Reporting group values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin Total
    Number of subjects
    		 315 318 633
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 61.0 (26 to 84) 60.0 (34 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 101 108 209
        Male
    		 214 210 424
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 47 46 93
        Not Hispanic or Latino
    		 268 272 540
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 8 9 17
        White
    		 292 298 590
        More than one race
    		 13 11 24
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Russian Federation
    		 16 13 29
        Romania
    		 21 31 52
        Hungary
    		 23 22 45
        United States
    		 0 1 1
        United Kingdom
    		 11 11 22
        Portugal
    		 6 1 7
        Spain
    		 40 27 67
        Greece
    		 5 10 15
        Canada
    		 2 1 3
        Austria
    		 8 11 19
        Belgium
    		 8 9 17
        Brazil
    		 37 35 72
        Poland
    		 28 24 52
        Italy
    		 17 19 36
        South Africa
    		 2 5 7
        Slovakia
    		 3 1 4
        Australia
    		 6 8 14
        France
    		 7 3 10
        Germany
    		 75 84 159
        Croatia
    		 0 2 2
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline
    Classifies participants according to their functional impairment. Scores range from 0 (Fully Active) to 5 (Death). 0 - Fully Active. 1 - Ambulatory, Restricted Strenuous Activity. 2 - Ambulatory, No Work Activities. 3 - Partially Confined to Bed, Limited Self Care. 4 - Completely Disabled. 5 - Death.
    Units: Subjects
        _0
    		 115 132 247
        _1
    		 183 166 349
        _2
    		 16 20 36
        Missing
    		 1 0 1
    Smoking
    Units: Subjects
        Ex-Light Smoker
    		 26 27 53
        Nonsmoker
    		 51 53 104
        Smoker
    		 238 238 476
    Disease Stage at Study Entry
    Stage means how big the tumor is and how far it has spread. Stages range from 0 (not spread) to IV (spread throughout the body). Stage IIIB - the cancer has spread to nearby tissue or spread to far away lymph nodes. Stage IV - the cancer has spread to other organs of the body such as the other lung, brain, or liver.
    Units: Subjects
        Stage IIIB
    		 9 11 20
        Stage IV
    		 305 307 612
        Missing
    		 1 0 1
    Disease Histology
    Units: Subjects
        Adenocarcinoma/Large Cell Carcinoma
    		 307 311 618
        Other
    		 7 7 14
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Necitumumab + Pemetrexed + Cisplatin
    Reporting group description
    		 Necitumumab + Pemetrexed + Cisplatin Necitumumab: 800 milligrams (mg) (absolute dose) on Days 1 and 8 of every 3-week cycle. Pemetrexed: 500 mg/square meter (mg/m2) intravenous (I.V.) on Day 1 of every 3-week cycle, for a maximum of six cycles. Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles.

    Reporting group title
    Pemetrexed + Cisplatin
    Reporting group description
    		 Pemetrexed + Cisplatin Pemetrexed: 500 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles. Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles.

    Subject analysis set title
    Necitumumab + Pemextrexed + Cisplatin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Necitumumab + Pemetrexed + Cisplatin Necitumumab: 800 mg (absolute dose) on Days 1 and 8 of every 3-week cycle, administered as an I.V. infusion Pemetrexed: 500 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, 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
    OS 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 using the Kaplan-Meier method. Analysis Population Description (APD): All randomized participants. Censored participants: Necitumumab + Pemetrexed + Cisplatin =79, Pemetrexed + Cisplatin=72
    End point type
    Primary
    End point timeframe
    Randomization to Death from Any Cause (Up to 31.6 Months)
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    315
    318
    Units: Months
        median (confidence interval 95%)
    11.3 (9.5 to 13.4)
    11.5 (10.1 to 13.1)
    Statistical analysis title
    		 Overall survival time (OS)
    Comparison groups
    Necitumumab + Pemetrexed + Cisplatin v Pemetrexed + Cisplatin
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9561
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.21

    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 measured progressive disease as defined by RECIST (Version 1.0), or death from any cause. Participants who die without a reported prior progression will be 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 participant was 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 30.4 Months) APD: All randomized participants. Censored participants: Necitumumab + Pemetrexed + Cisplatin=84, Pemetrexed + Cisplatin=79
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    315
    318
    Units: Months
        median (confidence interval 95%)
    5.6 (5.1 to 6.0)
    5.6 (4.8 to 5.7)
    Statistical analysis title
    		 Progression-Free Survival (PFS)
    Comparison groups
    Necitumumab + Pemetrexed + Cisplatin v Pemetrexed + Cisplatin
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6647
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.16

    Secondary: Percentage of Participants who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Tumor Response Rate [ORR])  

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    End point title
    		 Percentage of Participants who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Tumor 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 30.4 Months)
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    315
    318
    Units: percentage of participants
        number (confidence interval 95%)
    31.1 (26.3 to 36.4)
    32.1 (27.2 to 37.4)
    Statistical analysis title
    		 ORR
    Comparison groups
    Necitumumab + Pemetrexed + Cisplatin v Pemetrexed + Cisplatin
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7945
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.34

    Secondary: Time to Treatment Failure (TTF)

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    End point title
    		 Time to Treatment Failure (TTF)
    End point description
    TTF was defined as the time from study enrollment/randomization to the first observation of measured progressive disease, death from any cause, or early discontinuation of treatment or initiation of new anti-cancer therapies. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. Progressive Disease (PD) was defined as having at least a 20% increase in sum of longest diameter of target lesions. Time to treatment failure was censored at the date of the last follow-up visit for participants who did not discontinue early, who were still alive, and who have not progressed. APD: All randomized participants. Censored participants: Necitumumab + Pemetrexed + Cisplatin = 10, Pemetrexed + Cisplatin = 13
    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 30.4 Months)
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    315
    318
    Units: Months
        median (confidence interval 95%)
    3.5 (3.2 to 3.9)
    4.3 (3.3 to 4.8)
    Statistical analysis title
    		 Time to Treatment Failure (TTF)
    Comparison groups
    Necitumumab + Pemetrexed + Cisplatin v Pemetrexed + Cisplatin
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0459
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.39

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

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    End point title
    		 Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab [1]
    End point description
    APD: Participants who were randomized to necitumumab and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Predose Day 1 of Cycle 2,3,4,5 and 6 Prior to Necitumumab Infusion, Up to 23 Weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis were planned for participants who received Necitumumab only.
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin
    Number of subjects analysed
    315
    Units: micrograms/milliliter (ug/ml)
    geometric mean (geometric coefficient of variation)
        Predose Cycle 2 Day 1
    57.5 ( 84.5 )
        Predose Cycle 3 Day 1
    80.8 ( 89.3 )
        Predose Cycle 4 Day 1
    110 ( 82.9 )
        Predose Cycle 5 Day 1
    115 ( 81.8 )
        Predose Cycle 6 Day 1
    119 ( 68.9 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Serum Anti-Necitumumab Antibody Assessment (Immunogenicity)

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    End point title
    		 Number of Participants with Serum Anti-Necitumumab Antibody Assessment (Immunogenicity)
    End point description
    A participant was considered to have an anti-Necitumumab antibody response if anti-drug antibodies (ADA) were confirmed positive. Treatment emergent antibodies were defined as any anti-Necitumumab antibody titer equal to or greater than 4-fold the participant's baseline titer. APD: All randomized participants who received at least one dose of necitumumab and had evaluable antibody data.
    End point type
    Secondary
    End point timeframe
    Baseline to Study Completion (Up to 31.6 Months)
    End point values
    		 Necitumumab + Pemextrexed + Cisplatin
    Number of subjects analysed
    301
    Units: participants
    number (not applicable)
        1 Positive Titer
    37
        Antibodies Detected
    18
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Patient Reported Outcomes (PRO) using the European Quality of Life-5 Dimensions (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 Dimensions (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 + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    143
    147
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.0419 ( 0.28230 )
    0.0478 ( 0.22645 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in PRO as measured using the Lung Cancer Symptom Scale (LCSS)

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    End point title
    		 Mean Change from Baseline in PRO as measured using the 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.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 6 (Cycle =3 Weeks) APD: All randomized participants who had evaluable baseline and postbaseline LCSS data.
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    315
    318
    Units: millimeter (mm)
    arithmetic mean (standard deviation)
        Loss of Appetite
    4.6 ( 46.18 )
    0.6 ( 27.52 )
        Fatigue
    4.5 ( 31.24 )
    1.6 ( 28.75 )
        Cough
    -9.1 ( 31.08 )
    -10.3 ( 27.88 )
        Dyspnea
    -2.8 ( 26.32 )
    -1.5 ( 23.67 )
        Hemoptysis
    -1.1 ( 11.92 )
    -1.1 ( 7.81 )
        Pain
    -4.2 ( 27.22 )
    -7.1 ( 26.64 )
        Overall Symptoms
    -3.1 ( 31.22 )
    -7.4 ( 27.11 )
        Quality of Life
    2.5 ( 26.01 )
    -3.3 ( 24.91 )
        Interference
    3.2 ( 27.15 )
    -4.0 ( 31.39 )
        Average Symptom Burden Index (ASBI)
    -0.9 ( 18.35 )
    -3.1 ( 13.11 )
        LCSS Total Score
    0.1 ( 17.59 )
    -4.3 ( 13.90 )
    No statistical analyses for this end point

    Secondary: Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC)

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    End point title
    		 Epidermal Growth Factor Hormone (EGFR) Protein Expression Measured by Immunohistochemistry (IHC)
    End point description
    EGFR IHC H-score = weighted sum of % 1+ cells, twice % 2+ cells, and three times % 3+ cells. IHC H-score criteria assesses 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: Translational research population included all participants who: (1) received at least one dose of study drug; (2) had a valid non-missing result for EGFR H-Score; and (3) were enrolled for more than 2 cycles prior to the decision to terminate enrollment.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    245
    245
    Units: H-Score
    arithmetic mean (standard deviation)
        H-score <200
    69.06 ( 64.68 )
    66.23 ( 64.15 )
        H-score >=200
    259.35 ( 27.65 )
    256.26 ( 29.10 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with EGFR measured by IHC

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    End point title
    		 Percentage of Participants with EGFR measured by IHC
    End point description
    EGFR IHC H-score = weighted sum of % 1+ cells, twice % 2+ cells, and three times % 3+ cells. IHC H-score criteria assesses 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: Translational research population included all participants who: (1) received at least one dose of study drug; (2) had a valid non-missing result for EGFR H-Score; and (3) were enrolled for more than 2 cycles prior to the decision to terminate enrollment
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Necitumumab + Pemetrexed + Cisplatin Pemetrexed + Cisplatin
    Number of subjects analysed
    245
    245
    Units: percentage of participants
    number (not applicable)
        H-score <200
    58.8
    59.6
        H-score >=200
    41.2
    40.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    I4X-IE-JFCB
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Pemetrexed+Cisplatin
    Reporting group description
    		 Pemetrexed + Cisplatin Pemetrexed: 500 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles

    Reporting group title
    Necitumumab+Pemetrexed+Cisplatin
    Reporting group description
    		 Necitumumab + Pemetrexed + Cisplatin Necitumumab: 800 mg (absolute dose) on Days 1 and 8 of every 3-week cycle Pemetrexed: 500 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles Cisplatin: 75 mg/m2 I.V. on Day 1 of every 3-week cycle, for a maximum of six cycles

    Serious adverse events
    		 Pemetrexed+Cisplatin Necitumumab+Pemetrexed+Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    130 / 312 (41.67%)
    158 / 304 (51.97%)
         number of deaths (all causes)
    35
    53
         number of deaths resulting from adverse events
    10
    15
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    cancer pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant pleural effusion
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    metastases to central nervous system
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    metastatic pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    non-small cell lung cancer
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    10 / 312 (3.21%)
    24 / 304 (7.89%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 24
         deaths causally related to treatment / all
    0 / 9
    0 / 19
    tumour pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    aortic aneurysm rupture
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    arterial stenosis limb
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    arterial thrombosis limb
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    circulatory collapse
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    deep vein thrombosis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    embolism
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    hypertension
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    orthostatic hypotension
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral embolism
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral ischaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    poor venous access
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subclavian vein thrombosis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    superior vena caval occlusion
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombosis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis limb
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    analgesic therapy
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    3 / 3
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    1 / 3
    fatigue
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    7 / 312 (2.24%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    6 / 7
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    4 / 312 (1.28%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    4 / 5
    6 / 7
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    mucosal inflammation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    oedema peripheral
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    performance status decreased
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    systemic inflammatory response syndrome
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         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 pulmonary oedema
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    acute respiratory failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cough
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    epistaxis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    3 / 312 (0.96%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    pneumonitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary artery thrombosis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    11 / 312 (3.53%)
    13 / 304 (4.28%)
         occurrences causally related to treatment / all
    2 / 11
    10 / 13
         deaths causally related to treatment / all
    0 / 4
    2 / 3
    pulmonary haemorrhage
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    pulmonary oedema
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Psychiatric disorders
    agitation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    confusional state
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    international normalised ratio increased
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    weight decreased
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    drug administration error
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hip fracture
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         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 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lumbar vertebral fracture
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (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 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    procedural pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    suture rupture
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    angina pectoris
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    arrhythmia supraventricular
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    atrial fibrillation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial flutter
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac tamponade
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardio-respiratory arrest
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cardiomyopathy
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiopulmonary failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    myocardial infarction
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    pericardial effusion
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sinus tachycardia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tachycardia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral infarction
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral ischaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    cerebrovascular accident
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    4 / 312 (1.28%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    convulsion
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness postural
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hemiparesis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotonia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (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 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    migraine
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    paraesthesia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         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 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    13 / 312 (4.17%)
    12 / 304 (3.95%)
         occurrences causally related to treatment / all
    15 / 18
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    granulocytopenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    8 / 312 (2.56%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    8 / 8
    5 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    9 / 304 (2.96%)
         occurrences causally related to treatment / all
    5 / 5
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancytopenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    splenic infarction
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         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 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    6 / 6
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         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 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dental caries
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (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 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    10 / 304 (3.29%)
         occurrences causally related to treatment / all
    3 / 5
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenal ulcer
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenal ulcer haemorrhage
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enterocolitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         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 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus paralytic
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal infarction
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal perforation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    intra-abdominal haemorrhage
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    large intestine perforation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    6 / 312 (1.92%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    6 / 6
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal ulcer
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophagitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumatosis intestinalis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal haemorrhage
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    3 / 312 (0.96%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    volvulus
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    7 / 312 (2.24%)
    9 / 304 (2.96%)
         occurrences causally related to treatment / all
    7 / 7
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    biliary colic
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholecystitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    rash
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rash maculo-papular
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    toxic skin eruption
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urticaria
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    nephropathy toxic
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    6 / 312 (1.92%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    6 / 7
    5 / 5
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    renal failure acute
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal impairment
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bone pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    flank pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    musculoskeletal pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myalgia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain in extremity
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pathological fracture
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    abscess limb
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diverticulitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    erysipelas
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatitis b
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    herpes dermatitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    herpes oesophagitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal gangrene
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    neutropenic sepsis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    oral candidiasis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritoneal infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         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 12.0
         subjects affected / exposed
    6 / 312 (1.92%)
    14 / 304 (4.61%)
         occurrences causally related to treatment / all
    3 / 7
    4 / 14
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    pyelonephritis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    3 / 312 (0.96%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    septic shock
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    skin bacterial infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    staphylococcal infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    staphylococcal sepsis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    anorexia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    3 / 312 (0.96%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    3 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cachexia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    dehydration
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    8 / 8
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    electrolyte imbalance
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fluid retention
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperkalaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperuricaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypomagnesaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    1 / 312 (0.32%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    2 / 312 (0.64%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pemetrexed+Cisplatin Necitumumab+Pemetrexed+Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    303 / 312 (97.12%)
    296 / 304 (97.37%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    29 / 312 (9.29%)
    17 / 304 (5.59%)
         occurrences all number
    41
    24
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    68 / 312 (21.79%)
    88 / 304 (28.95%)
         occurrences all number
    146
    192
    fatigue
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    95 / 312 (30.45%)
    87 / 304 (28.62%)
         occurrences all number
    171
    164
    mucosal inflammation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    27 / 312 (8.65%)
    50 / 304 (16.45%)
         occurrences all number
    36
    104
    non-cardiac chest pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    16 / 312 (5.13%)
    11 / 304 (3.62%)
         occurrences all number
    22
    16
    oedema peripheral
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    41 / 312 (13.14%)
    40 / 304 (13.16%)
         occurrences all number
    51
    52
    pyrexia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    22 / 312 (7.05%)
    46 / 304 (15.13%)
         occurrences all number
    32
    57
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    48 / 312 (15.38%)
    56 / 304 (18.42%)
         occurrences all number
    59
    75
    dyspnoea
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    41 / 312 (13.14%)
    46 / 304 (15.13%)
         occurrences all number
    52
    62
    epistaxis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    9 / 312 (2.88%)
    21 / 304 (6.91%)
         occurrences all number
    9
    30
    haemoptysis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    10 / 312 (3.21%)
    21 / 304 (6.91%)
         occurrences all number
    12
    30
    productive cough
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    7 / 312 (2.24%)
    16 / 304 (5.26%)
         occurrences all number
    9
    17
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    10 / 312 (3.21%)
    18 / 304 (5.92%)
         occurrences all number
    11
    20
    insomnia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    15 / 312 (4.81%)
    17 / 304 (5.59%)
         occurrences all number
    20
    23
    Investigations
    blood creatinine increased
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    18 / 312 (5.77%)
    21 / 304 (6.91%)
         occurrences all number
    23
    34
    weight decreased
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    24 / 312 (7.69%)
    39 / 304 (12.83%)
         occurrences all number
    28
    53
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    26 / 312 (8.33%)
    38 / 304 (12.50%)
         occurrences all number
    37
    52
    dysgeusia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    32 / 312 (10.26%)
    21 / 304 (6.91%)
         occurrences all number
    43
    27
    headache
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    27 / 312 (8.65%)
    30 / 304 (9.87%)
         occurrences all number
    32
    41
    paraesthesia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    8 / 312 (2.56%)
    16 / 304 (5.26%)
         occurrences all number
    9
    20
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    91 / 312 (29.17%)
    72 / 304 (23.68%)
         occurrences all number
    200
    155
    leukopenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    36 / 312 (11.54%)
    45 / 304 (14.80%)
         occurrences all number
    61
    92
    lymphopenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    17 / 312 (5.45%)
    16 / 304 (5.26%)
         occurrences all number
    26
    53
    neutropenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    99 / 312 (31.73%)
    92 / 304 (30.26%)
         occurrences all number
    217
    179
    thrombocytopenia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    23 / 312 (7.37%)
    22 / 304 (7.24%)
         occurrences all number
    42
    43
    Ear and labyrinth disorders
    tinnitus
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    16 / 312 (5.13%)
    15 / 304 (4.93%)
         occurrences all number
    18
    18
    Eye disorders
    conjunctivitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    6 / 312 (1.92%)
    31 / 304 (10.20%)
         occurrences all number
    6
    46
    lacrimation increased
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    17 / 312 (5.45%)
    4 / 304 (1.32%)
         occurrences all number
    17
    4
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    15 / 312 (4.81%)
    19 / 304 (6.25%)
         occurrences all number
    15
    25
    abdominal pain upper
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    25 / 312 (8.01%)
    26 / 304 (8.55%)
         occurrences all number
    29
    36
    constipation
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    83 / 312 (26.60%)
    91 / 304 (29.93%)
         occurrences all number
    124
    133
    diarrhoea
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    51 / 312 (16.35%)
    90 / 304 (29.61%)
         occurrences all number
    78
    148
    dyspepsia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    18 / 312 (5.77%)
    16 / 304 (5.26%)
         occurrences all number
    28
    21
    nausea
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    183 / 312 (58.65%)
    174 / 304 (57.24%)
         occurrences all number
    403
    392
    stomatitis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    12 / 312 (3.85%)
    30 / 304 (9.87%)
         occurrences all number
    22
    41
    vomiting
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    104 / 312 (33.33%)
    105 / 304 (34.54%)
         occurrences all number
    180
    213
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    18 / 312 (5.77%)
    29 / 304 (9.54%)
         occurrences all number
    20
    31
    dermatitis acneiform
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    42 / 304 (13.82%)
         occurrences all number
    0
    119
    dry skin
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    11 / 312 (3.53%)
    43 / 304 (14.14%)
         occurrences all number
    13
    62
    hirsutism
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed [1]
    0 / 107 (0.00%)
    5 / 95 (5.26%)
         occurrences all number
    0
    5
    pruritus
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    8 / 312 (2.56%)
    31 / 304 (10.20%)
         occurrences all number
    9
    48
    rash
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    20 / 312 (6.41%)
    125 / 304 (41.12%)
         occurrences all number
    23
    346
    rash generalised
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    28 / 304 (9.21%)
         occurrences all number
    5
    62
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    20 / 312 (6.41%)
    33 / 304 (10.86%)
         occurrences all number
    24
    40
    musculoskeletal pain
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    15 / 312 (4.81%)
    19 / 304 (6.25%)
         occurrences all number
    21
    26
    pain in extremity
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    17 / 312 (5.45%)
    18 / 304 (5.92%)
         occurrences all number
    19
    22
    Infections and infestations
    oral candidiasis
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    5 / 312 (1.60%)
    18 / 304 (5.92%)
         occurrences all number
    5
    22
    paronychia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    0 / 312 (0.00%)
    28 / 304 (9.21%)
         occurrences all number
    0
    67
    urinary tract infection
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    16 / 312 (5.13%)
    19 / 304 (6.25%)
         occurrences all number
    21
    21
    Metabolism and nutrition disorders
    anorexia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    97 / 312 (31.09%)
    110 / 304 (36.18%)
         occurrences all number
    171
    174
    fluid retention
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    12 / 312 (3.85%)
    17 / 304 (5.59%)
         occurrences all number
    22
    39
    hyperglycaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    10 / 312 (3.21%)
    16 / 304 (5.26%)
         occurrences all number
    15
    34
    hypocalcaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    13 / 312 (4.17%)
    30 / 304 (9.87%)
         occurrences all number
    16
    51
    hypomagnesaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    36 / 312 (11.54%)
    75 / 304 (24.67%)
         occurrences all number
    66
    185
    hypokalaemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    23 / 312 (7.37%)
    20 / 304 (6.58%)
         occurrences all number
    33
    34
    hyponatraemia
    alternative dictionary used: MedDRA 12.0
         subjects affected / exposed
    20 / 312 (6.41%)
    23 / 304 (7.57%)
         occurrences all number
    30
    36
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2011
    Amendment v.5.0: The enrollment for this study was early terminated following Independent Data Monitoring Committee (IDMC) recommendations, due to an increased rate of serious thromboembolic (TE) events in the treatment arm with Necitumumab.

    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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