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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study of Weekly Paclitaxel With or Without Ramucirumab (IMC-1121B) Drug Product in Patients With Metastatic Gastric Adenocarcinoma, Refractory to or Progressive After First-Line Therapy With Platinum and Fluoropyrimidine

    Summary
    EudraCT number
    2010-020426-18
    Trial protocol
    DE   ES   HU   RO   FR   GB   AT   LT   PT   EE   IT   BE   BG  
    Global end of trial date
    20 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Mar 2018
    First version publication date
    05 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I4T-IE-JVBE
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01170663
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial ID: 13894
    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
    20 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a Phase III randomized multicenter double-blind, placebo controlled trial evaluating the safety and efficacy of paclitaxel plus ramucirumab (IMC-1211B) drug product (DP) compared to paclitaxel plus placebo.
    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
    06 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Taiwan: 30
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 41
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 140
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 45
    Country: Number of subjects enrolled
    Lithuania: 12
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Singapore: 5
    Worldwide total number of subjects
    665
    EEA total number of subjects
    282
    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)
    418
    From 65 to 84 years
    247
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    No Text Entered

    Pre-assignment
    Screening details
    One (1) participant was randomized to the placebo/paclitaxel group but had ramucirumab (IMC-1121B) in error. For the Intent-to-Treat (ITT) population this participant was included in the placebo/paclitaxel treatment group and for the Safety population (Pop) this participant was included in ramucirumab (IMC-1121B)/paclitaxel treatment group.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Completers include participants that discontinued study drugs either due to progressive disease (PD), due to an adverse event or died due to any cause, but not necessarily had any survival-FU assessment done.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Arm description
    8 milligrams/kilogram (mg/kg) of ramucirumab (IMC-1121B) was administered by intravenous (IV) infusion on Days 1 and 15 in combination with 80 milligrams/square meter (mg/m²) paclitaxel administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    IMC-1211B
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligrams/kilogram (mg/kg) of ramucirumab (IMC-1121B) was administered by intravenous (IV) infusion on Days 1 and 15 in combination with 80 milligrams/square meter (mg/m²) paclitaxel administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligrams/kilogram (mg/kg) of ramucirumab (IMC-1121B) was administered by intravenous (IV) infusion on Days 1 and 15 in combination with 80 milligrams/square meter (mg/m²) paclitaxel administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Arm title
    Placebo plus Paclitaxel
    Arm description
    Placebo was administered by IV infusion on Days 1 and 15, in combination with 80 mg/m² paclitaxel administered on Days 1, 8, and 15 of a 28-day cycle.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered by IV infusion on Days 1 and 15, in combination with 80 mg/m² paclitaxel administered on Days 1, 8, and 15 of a 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered by IV infusion on Days 1 and 15 in combination with 80 mg/m² paclitaxel administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Number of subjects in period 1
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Started
    330
    335
    Received any treatment (Safety Pop)
    327
    329
    Completed
    316
    315
    Not completed
    14
    20
         Withdrawal of consent without follow-up
    11
    11
         Lost to follow-up
    3
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Reporting group description
    8 milligrams/kilogram (mg/kg) of ramucirumab (IMC-1121B) was administered by intravenous (IV) infusion on Days 1 and 15 in combination with 80 milligrams/square meter (mg/m²) paclitaxel administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Reporting group title
    Placebo plus Paclitaxel
    Reporting group description
    Placebo was administered by IV infusion on Days 1 and 15, in combination with 80 mg/m² paclitaxel administered on Days 1, 8, and 15 of a 28-day cycle.

    Reporting group values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel Total
    Number of subjects
    330 335 665
    Age Categorical
    Units: Participants
        <=18 years
    0 0 0
        Between 18 and 65 years
    205 213 418
        >=65 years
    125 122 247
    Age Continuous
    Units: years
        median (full range (min-max))
    61 (25 to 83) 61 (24 to 84) -
    Gender, Male/Female
    Units: Participants
        Female
    101 92 193
        Male
    229 243 472
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    31 26 57
        Not Hispanic or Latino
    299 309 608
        Unknown or Not Reported
    0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    110 121 231
        Black or African American
    6 6 12
        White
    208 199 407
        More than one race
    0 1 1
        Other
    6 7 13
    Region of Enrollment
    Units: Subjects
        Portugal
    2 0 2
        United States
    12 12 24
        Estonia
    5 5 10
        Taiwan
    14 16 30
        Spain
    8 13 21
        Russian Federation
    8 13 21
        Chile
    1 3 4
        Italy
    13 15 28
        France
    20 14 34
        Australia
    18 23 41
        Korea, Republic of
    23 22 45
        Lithuania
    6 6 12
        Austria
    4 2 6
        United Kingdom
    6 9 15
        Hungary
    20 9 29
        Mexico
    2 2 4
        Argentina
    1 0 1
        Poland
    15 18 33
        Brazil
    19 16 35
        Belgium
    12 14 26
        Singapore
    2 3 5
        Romania
    7 7 14
        Bulgaria
    7 5 12
        Germany
    20 20 40
        Japan
    68 72 140
        Hong Kong
    2 1 3
        Israel
    15 15 30

    End points

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    End points reporting groups
    Reporting group title
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Reporting group description
    8 milligrams/kilogram (mg/kg) of ramucirumab (IMC-1121B) was administered by intravenous (IV) infusion on Days 1 and 15 in combination with 80 milligrams/square meter (mg/m²) paclitaxel administered by IV infusion on Days 1, 8, and 15 of a 28-day cycle.

    Reporting group title
    Placebo plus Paclitaxel
    Reporting group description
    Placebo was administered by IV infusion on Days 1 and 15, in combination with 80 mg/m² paclitaxel administered on Days 1, 8, and 15 of a 28-day cycle.

    Primary: Overall Survival Time (OS)

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    End point title
    Overall Survival Time (OS)
    End point description
    OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive.
    End point type
    Primary
    End point timeframe
    Randomization up to 27.5 months
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    330 [1]
    335 [2]
    Units: months
        median (confidence interval 95%)
    9.6 (8.5 to 10.8)
    7.4 (6.3 to 8.4)
    Notes
    [1] - Participants censored: Ramucirumab (IMC-1211B) plus Paclitaxel =74, Placebo plus Paclitaxel =75.
    [2] - Participants censored: Ramucirumab (IMC-1211B) plus Paclitaxel =74, Placebo plus Paclitaxel =75.
    Statistical analysis title
    Overall Survival Statistical Analysis
    Comparison groups
    Ramucirumab (IMC-1211B) plus Paclitaxel v Placebo plus Paclitaxel
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0169 [3]
    Method
    Stratified Log Rank Test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.807
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.678
         upper limit
    0.962
    Notes
    [3] - Adjusted for stratification factors: geographic region, time-to-progression from start of first-line therapy and disease measurability.

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS was measured from date of randomization to first radiographically documented progressive disease (PD) or death due to any cause. PD defined using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. Participants who had no baseline or post baseline radiological tumor assessment were censored at date of randomization. Participants who had no tumor progression or death within 2 scan intervals following the last assessment were censored at the date of last radiographic tumor assessment. Participants who began new anticancer treatment and had no tumor progression were censored at date of assessment prior to initiation of new therapy. Participants lost to follow-up or withdrew consent were censored at the date of their last assessment.
    End point type
    Secondary
    End point timeframe
    Randomization up to 22.2 months
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    330 [4]
    335 [5]
    Units: months
        median (confidence interval 95%)
    4.4 (4.2 to 5.3)
    2.9 (2.8 to 3.0)
    Notes
    [4] - Participants censored: Ramucirumab (IMC-1211B) plus Paclitaxel =51, Placebo plus Paclitaxel =39.
    [5] - Participants censored: Ramucirumab (IMC-1211B) plus Paclitaxel =51, Placebo plus Paclitaxel =39.
    Statistical analysis title
    Progression-Free Survival Statistical Analysis
    Comparison groups
    Ramucirumab (IMC-1211B) plus Paclitaxel v Placebo plus Paclitaxel
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Stratified Log Rank Test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.635
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.536
         upper limit
    0.752
    Notes
    [6] - Adjusted for stratification factors: geographic region, time-to-progression from start of first-line therapy and disease measurability.

    Secondary: Time to Progressive Disease (TTP)

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    End point title
    Time to Progressive Disease (TTP)
    End point description
    TTP was defined as the time from randomization until date of radiographic progression using RECIST v1.1 criteria. PD was defined as having a ≥20% increase in sum of longest diameter (LD) of target lesions and at minimum 5 millimeters (mm) increase above nadir. Participants who did not progress or were lost to follow-up were censored at the date of last tumor assessment. Participants who had no baseline tumor assessment or no post baseline assessment and no death reported with 2 scan intervals post randomization were censored at date of randomization. Participants with no progression and not died within 2 scan intervals after last assessment were censored at date of last tumor assessment. Participants with no post baseline assessment or tumor progression but death reported within 2 scan intervals after randomization were censored at date of death.
    End point type
    Secondary
    End point timeframe
    Baseline up to 22.2 months
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    330 [7]
    335 [8]
    Units: months
        median (confidence interval 95%)
    5.52 (4.50 to 5.68)
    3.02 (2.86 to 4.14)
    Notes
    [7] - Participants censored: Ramucirumab (IMC-1211B) plus Paclitaxel =107, Placebo plus Paclitaxel =94.
    [8] - Participants censored: Ramucirumab (IMC-1211B) plus Paclitaxel =107, Placebo plus Paclitaxel =94.
    Statistical analysis title
    Time to Progression Statistical Analysis
    Comparison groups
    Ramucirumab (IMC-1211B) plus Paclitaxel v Placebo plus Paclitaxel
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Stratified Log Rank Test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.596
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.494
         upper limit
    0.72
    Notes
    [9] - Adjusted for stratification factors: geographic region, time-to-progression from start of first-line therapy and disease measurability.

    Secondary: Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or PD

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    End point title
    Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or PD
    End point description
    BOR was defined as the best response across all time points from randomization until radiologically confirmed PD using RECIST, v1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and normalization of tumor marker level of non-target lesions. PR was defined as having a ≥30% decrease in sum of LD of target lesions. PD was defined as having a ≥20% increase in sum of LD of target lesions and ≥5 mm increase above nadir. SD was defined as small changes that did not meet above criteria.
    End point type
    Secondary
    End point timeframe
    Randomization up to 22.2 months
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    330 [10]
    335 [11]
    Units: percentage of participants
    number (not applicable)
        CR
    0.6
    0.3
        PR
    27.3
    15.8
        SD
    52.1
    47.5
        PD
    13.0
    24.8
        Not Evaluable
    0.3
    0.9
        No Tumor Response Evaluation
    6.7
    10.7
    Notes
    [10] - All randomized participants.
    [11] - All randomized participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CR or PR [Objective Response Rate (ORR)]

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    End point title
    Percentage of Participants with CR or PR [Objective Response Rate (ORR)]
    End point description
    ORR was the percentage of participants who had CR or PR defined using RECIST v1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and normalization of tumor marker level of non-target lesions. PR was defined as having a ≥30% decrease in sum of LD of target lesions. Percentage of participants calculated as: (number of participants with CR + PR)/(total number of participants)*100.
    End point type
    Secondary
    End point timeframe
    Randomization up to 22.2 months
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    330 [12]
    335 [13]
    Units: percentage of participants
        number (confidence interval 95%)
    27.9 (23.3 to 33.0)
    16.1 (12.6 to 20.4)
    Notes
    [12] - All randomized participants.
    [13] - All randomized participants.
    Statistical analysis title
    Objective Response Rate Statistical Analysis
    Comparison groups
    Ramucirumab (IMC-1211B) plus Paclitaxel v Placebo plus Paclitaxel
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.45
         upper limit
    3.16
    Notes
    [14] - Adjusted for stratification factors: geographic region, time-to-progression from the start of first-line therapy and disease measurability.

    Secondary: Percentage of Participants with Anti-Ramucirumab Antibodies (Serum Anti-Ramucirumab Antibody Assessment) (Immunogenicity)

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    End point title
    Percentage of Participants with Anti-Ramucirumab Antibodies (Serum Anti-Ramucirumab Antibody Assessment) (Immunogenicity)
    End point description
    Participants who developed treatment-emergent antibody responses to Ramucirumab (IMC-1121B) after baseline.
    End point type
    Secondary
    End point timeframe
    Prior to and after ramucirumab (IMC-1121B) infusion: Day 1 Cycles 1, 2 and 3 (28-day cycles) Doses 1, 4, 7 and 30-37 days after last dose of study therapy up to 103 weeks
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    320 [15]
    323 [16]
    Units: percentage of participants
        number (not applicable)
    1.6
    0.3
    Notes
    [15] - All randomized participants who received at least one dose of study drug and developed antibodies.
    [16] - All randomized participants who received at least one dose of study drug and developed antibodies.
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) after First Ramucirumab (IMC-1211B) Infusion

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    End point title
    Maximum Concentration (Cmax) after First Ramucirumab (IMC-1211B) Infusion [17]
    End point description
    The inter-patient variability is reported as the geometric coefficient of variation (%). Geometric mean and coefficient of variation (CV) is reported as a number and not a decimal or percentage.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1, 1 hour post end of infusion (28-day cycles)
    Notes
    [17] - 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: pharmacokinetics was not assessed for the placebo/paclitaxel arm.
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Number of subjects analysed
    259 [18]
    Units: micrograms/milliliter (µg/mL)
        geometric mean (geometric coefficient of variation)
    146 ( 28 )
    Notes
    [18] - All participants who received Ramucirumab (IMC-1121B) plus Paclitaxel and had Cmax observed.
    No statistical analyses for this end point

    Secondary: Cmax after 4th Ramucirumab (IMC-1211B) Infusion

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    End point title
    Cmax after 4th Ramucirumab (IMC-1211B) Infusion [19]
    End point description
    The inter-patient variability is reported as the geometric coefficient of variation (%). Geometric mean and coefficient of variation (CV) is reported as a number and not a decimal or percentage.
    End point type
    Secondary
    End point timeframe
    Cycle 2, Day 15 1 hour post end of infusion (28-day cycles)
    Notes
    [19] - 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: pharmacokinetics was not assessed for the placebo/paclitaxel arm.
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Number of subjects analysed
    200
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    193 ( 34 )
    No statistical analyses for this end point

    Secondary: Cmax after 7th Ramucirumab (IMC-1211B) Infusion

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    End point title
    Cmax after 7th Ramucirumab (IMC-1211B) Infusion [20]
    End point description
    The inter-patient variability is reported as the geometric coefficient of variation (%). Geometric mean and coefficient of variation (CV) is reported as a number and not a decimal or percentage.
    End point type
    Secondary
    End point timeframe
    Cycle 4, Day 1, 1 hour post end of infusion (28-day cycles)
    Notes
    [20] - 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: pharmacokinetics was not assessed for the placebo/paclitaxel arm.
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Number of subjects analysed
    127 [21]
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    216 ( 30 )
    Notes
    [21] - All participants who received Ramucirumab (IMC-1121B) plus Paclitaxel and had Cmax observations.
    No statistical analyses for this end point

    Secondary: Minimum Concentration (Cmin) Prior to First Ramucirumab (IMC-1211B) Infusion

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    End point title
    Minimum Concentration (Cmin) Prior to First Ramucirumab (IMC-1211B) Infusion [22]
    End point description
    This outcome measure was included in error as the time point was before ramucirumab (IMC-1211B) was administered. Cmin was not analyzed.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1 predose (28-day cycles)
    Notes
    [22] - 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: pharmacokinetics was not assessed for the placebo/paclitaxel arm.
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Number of subjects analysed
    0 [23]
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [23] - Zero participants were analyzed and no data is available.
    No statistical analyses for this end point

    Secondary: Cmin Prior to 4th Ramucirumab (IMC-1211B) Infusion

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    End point title
    Cmin Prior to 4th Ramucirumab (IMC-1211B) Infusion [24]
    End point description
    The inter-patient variability is reported as the geometric coefficient of variation (%). Geometric mean and coefficient of variation (CV) is reported as a number and not a decimal or percentage.
    End point type
    Secondary
    End point timeframe
    Cycle 2, Day 15 (28-day cycle)
    Notes
    [24] - 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: pharmacokinetics was not assessed for the placebo/paclitaxel arm.
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Number of subjects analysed
    203 [25]
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    45.0 ( 50 )
    Notes
    [25] - All participants who received Ramucirumab (IMC-1121B) plus Paclitaxel and had Cmin observations.
    No statistical analyses for this end point

    Secondary: Cmin Prior to 7th Ramucirumab (IMC-1211B) Infusion

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    End point title
    Cmin Prior to 7th Ramucirumab (IMC-1211B) Infusion [26]
    End point description
    The inter-patient variability is reported as the geometric coefficient of variation (%). Geometric mean and coefficient of variation (CV) is reported as a number and not a decimal or percentage.
    End point type
    Secondary
    End point timeframe
    Cycle 4, Day 1 (28-day cycles)
    Notes
    [26] - 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: pharmacokinetics was not assessed for the placebo/paclitaxel arm.
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel
    Number of subjects analysed
    142 [27]
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    62.8 ( 47 )
    Notes
    [27] - All participants who received Ramucirumab (IMC-1121B) plus Paclitaxel and had Cmin observations.
    No statistical analyses for this end point

    Secondary: Change from Baseline to End of Therapy in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life: Questionnaire (QLQ-C30) in Global Health Status

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    End point title
    Change from Baseline to End of Therapy in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life: Questionnaire (QLQ-C30) in Global Health Status
    End point description
    EORTC QLQ-C30 v3.0 is a 30-item, self-administered questionnaire with multidimensional scales assessing 15 domains (5 functional domains [physical, role, cognitive, emotional, and social], 9 symptom scales [fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties] and global health status scale). 28 questions assessed on a 1 (not at all) to 4 (very much) scale and the remaining 2 questions used a 1 (poor) to 7 (excellent) scale. A linear transformation was applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For the functional domains and global health status scale, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, end of therapy (up to 103 weeks)
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    209 [28]
    202 [29]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -13.5 ( 23.24 )
    -12.1 ( 24.81 )
    Notes
    [28] - All randomized participants with global health status observations.
    [29] - All randomized participants with global health status observations.
    Statistical analysis title
    Questionnaire Statistical Analysis
    Comparison groups
    Ramucirumab (IMC-1211B) plus Paclitaxel v Placebo plus Paclitaxel
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3973 [30]
    Method
    ANCOVA
    Confidence interval
    Notes
    [30] - Analysis of covariance (ANCOVA) included treatment group, randomization stratification factors and baseline value of Global Health Status scale.

    Secondary: Change from Baseline to End of Therapy in European Quality of Life Questionnaire-5 Dimension (EuroQol EQ-5D) Index Score

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    End point title
    Change from Baseline to End of Therapy in European Quality of Life Questionnaire-5 Dimension (EuroQol EQ-5D) Index Score
    End point description
    The EQ-5D is a generic, multidimensional, health status instrument. The profile allowed participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale [1 (no problem), 2 (some problems), and 3 (major problems)]. These combinations of responses 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). A negative change indicated a worsening of the participant's health status.
    End point type
    Secondary
    End point timeframe
    Baseline, end of therapy (up to 103 weeks)
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    205 [31]
    201 [32]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.16 ( 0.279 )
    -0.19 ( 0.337 )
    Notes
    [31] - All randomized participants with EQ-5D observations.
    [32] - All randomized participants with EQ-5D observations.
    No statistical analyses for this end point

    Other pre-specified: Number of Participants with Serious and Other Non-Serious Adverse Events (AE) and Who Died

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    End point title
    Number of Participants with Serious and Other Non-Serious Adverse Events (AE) and Who Died
    End point description
    Participants who died or who had clinically significant events defined as serious AEs (SAEs) and other non-serious AEs (regardless of causality). A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 103 weeks and within 30 days of last dose of study drug
    End point values
    Ramucirumab (IMC-1211B) plus Paclitaxel Placebo plus Paclitaxel
    Number of subjects analysed
    327 [33]
    329 [34]
    Units: participants
    number (not applicable)
        SAEs
    161
    146
        Other Non-serious AEs
    324
    321
        Died
    37
    52
    Notes
    [33] - All randomized participants who received at least one dose of study drug.
    [34] - All randomized participants who received at least one dose of study drug.
    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
    I4T-IE-JVBE
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Paclitaxel plus Ramucirumab
    Reporting group description
    -

    Reporting group title
    Paclitaxel plus Placebo
    Reporting group description
    -

    Serious adverse events
    Paclitaxel plus Ramucirumab Paclitaxel plus Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    161 / 327 (49.24%)
    146 / 329 (44.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    brain cancer metastatic
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cancer pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant ascites
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant neoplasm progression
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    48 / 327 (14.68%)
    49 / 329 (14.89%)
         occurrences causally related to treatment / all
    0 / 65
    0 / 66
         deaths causally related to treatment / all
    0 / 37
    0 / 39
    malignant pleural effusion
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to central nervous system
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to liver
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to meninges
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to spine
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal cancer
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tumour pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    arteriosclerosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    deep vein thrombosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypovolaemic shock
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    vein disorder
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vena cava thrombosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    device dislocation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    disease progression
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    drowning
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    fatigue
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    7 / 329 (2.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    feeling abnormal
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    8 / 327 (2.45%)
    9 / 329 (2.74%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    injection site injury
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oedema peripheral
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    8 / 327 (2.45%)
    7 / 329 (2.13%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    aspiration
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    dyspnoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gynaecomastia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed [1]
    1 / 226 (0.44%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoxia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infiltration
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    pneumonitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    respiratory failure
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anticoagulation drug level above therapeutic
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood creatinine increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    blood urea increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    clavicle fracture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis radiation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    incisional hernia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    splenic rupture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    pyloric stenosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    acute coronary syndrome
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         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 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial flutter
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial thrombosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    extrasystoles
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    akathisia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cerebral infarction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebrovascular accident
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coma
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hydrocephalus
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intracranial pressure increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ischaemic stroke
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal cord compression
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    8 / 327 (2.45%)
    7 / 329 (2.13%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    disseminated intravascular coagulation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    8 / 327 (2.45%)
    5 / 329 (1.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    leukopenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    12 / 327 (3.67%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    hearing impaired
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vertigo
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    cataract
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lacrimation increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    10 / 327 (3.06%)
    11 / 329 (3.34%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain upper
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    aphagia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diverticular perforation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    4 / 327 (1.22%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    4 / 327 (1.22%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    gastrointestinal obstruction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal perforation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    haematemesis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ileus paralytic
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    intestinal ischaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    6 / 327 (1.83%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal perforation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malabsorption
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    melaena
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mouth ulceration
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    5 / 329 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    obstruction gastric
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    odynophagia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal food impaction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal perforation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal spasm
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal stenosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal ulcer
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophagitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis acute
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumatosis intestinalis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal stenosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subileus
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    7 / 327 (2.14%)
    10 / 329 (3.04%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct obstruction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholecystitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholecystitis acute
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    jaundice
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    jaundice cholestatic
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    azotaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysuria
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hydronephrosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    obstructive uropathy
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure acute
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    urinary retention
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    inappropriate antidiuretic hormone secretion
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    flank pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myalgia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain in extremity
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pathological fracture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    anal abscess
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    appendicitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bacteraemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    biliary sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    biliary tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchopneumonia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea infectious
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    endocarditis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    influenza
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lobar pneumonia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    localised infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    lung infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenic sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    perirectal abscess
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis bacterial
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudomonas infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 327 (1.53%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    septic shock
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    staphylococcal infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    staphylococcal sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection bacterial
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urosepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    viral infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    cachexia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    decreased appetite
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 327 (0.61%)
    5 / 329 (1.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    6 / 327 (1.83%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoalbuminaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 327 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hyponatraemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 327 (0.92%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypophagia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 327 (0.31%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. 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.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Paclitaxel plus Ramucirumab Paclitaxel plus Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    324 / 327 (99.08%)
    321 / 329 (97.57%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    malignant neoplasm progression
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    15 / 327 (4.59%)
    26 / 329 (7.90%)
         occurrences all number
    15
    26
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    80 / 327 (24.46%)
    16 / 329 (4.86%)
         occurrences all number
    159
    25
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    69 / 327 (21.10%)
    44 / 329 (13.37%)
         occurrences all number
    186
    72
    fatigue
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    128 / 327 (39.14%)
    104 / 329 (31.61%)
         occurrences all number
    282
    221
    oedema peripheral
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    81 / 327 (24.77%)
    45 / 329 (13.68%)
         occurrences all number
    121
    58
    pyrexia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    54 / 327 (16.51%)
    35 / 329 (10.64%)
         occurrences all number
    81
    53
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    42 / 327 (12.84%)
    26 / 329 (7.90%)
         occurrences all number
    49
    35
    dysphonia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    17 / 327 (5.20%)
    9 / 329 (2.74%)
         occurrences all number
    22
    13
    dyspnoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    42 / 327 (12.84%)
    31 / 329 (9.42%)
         occurrences all number
    63
    38
    epistaxis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    100 / 327 (30.58%)
    23 / 329 (6.99%)
         occurrences all number
    157
    34
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    31 / 327 (9.48%)
    26 / 329 (7.90%)
         occurrences all number
    32
    27
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    21 / 327 (6.42%)
    18 / 329 (5.47%)
         occurrences all number
    43
    22
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    28 / 327 (8.56%)
    17 / 329 (5.17%)
         occurrences all number
    63
    23
    weight decreased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    45 / 327 (13.76%)
    49 / 329 (14.89%)
         occurrences all number
    81
    69
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    20 / 327 (6.12%)
    13 / 329 (3.95%)
         occurrences all number
    25
    16
    dysgeusia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    29 / 327 (8.87%)
    21 / 329 (6.38%)
         occurrences all number
    33
    23
    headache
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    34 / 327 (10.40%)
    22 / 329 (6.69%)
         occurrences all number
    52
    37
    neuropathy peripheral
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    47 / 327 (14.37%)
    30 / 329 (9.12%)
         occurrences all number
    88
    51
    paraesthesia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    24 / 327 (7.34%)
    25 / 329 (7.60%)
         occurrences all number
    42
    41
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    57 / 327 (17.43%)
    36 / 329 (10.94%)
         occurrences all number
    123
    63
    polyneuropathy
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    18 / 327 (5.50%)
    22 / 329 (6.69%)
         occurrences all number
    31
    38
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    111 / 327 (33.94%)
    116 / 329 (35.26%)
         occurrences all number
    264
    276
    leukopenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    110 / 327 (33.64%)
    69 / 329 (20.97%)
         occurrences all number
    470
    201
    neutropenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    173 / 327 (52.91%)
    102 / 329 (31.00%)
         occurrences all number
    877
    253
    thrombocytopenia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    41 / 327 (12.54%)
    20 / 329 (6.08%)
         occurrences all number
    102
    37
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    22 / 327 (6.73%)
    20 / 329 (6.08%)
         occurrences all number
    28
    25
    abdominal pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    98 / 327 (29.97%)
    61 / 329 (18.54%)
         occurrences all number
    165
    103
    abdominal pain upper
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    34 / 327 (10.40%)
    35 / 329 (10.64%)
         occurrences all number
    57
    52
    ascites
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    31 / 327 (9.48%)
    25 / 329 (7.60%)
         occurrences all number
    46
    38
    constipation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    71 / 327 (21.71%)
    71 / 329 (21.58%)
         occurrences all number
    94
    89
    diarrhoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    103 / 327 (31.50%)
    76 / 329 (23.10%)
         occurrences all number
    249
    127
    dyspepsia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    17 / 327 (5.20%)
    16 / 329 (4.86%)
         occurrences all number
    19
    18
    dysphagia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    19 / 327 (5.81%)
    17 / 329 (5.17%)
         occurrences all number
    28
    18
    nausea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    116 / 327 (35.47%)
    106 / 329 (32.22%)
         occurrences all number
    238
    183
    stomatitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    64 / 327 (19.57%)
    24 / 329 (7.29%)
         occurrences all number
    103
    33
    vomiting
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    86 / 327 (26.30%)
    65 / 329 (19.76%)
         occurrences all number
    142
    111
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    107 / 327 (32.72%)
    127 / 329 (38.60%)
         occurrences all number
    137
    159
    dry skin
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    25 / 327 (7.65%)
    10 / 329 (3.04%)
         occurrences all number
    28
    10
    pruritus
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    21 / 327 (6.42%)
    11 / 329 (3.34%)
         occurrences all number
    24
    13
    rash
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    35 / 327 (10.70%)
    25 / 329 (7.60%)
         occurrences all number
    44
    28
    Renal and urinary disorders
    proteinuria
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    55 / 327 (16.82%)
    20 / 329 (6.08%)
         occurrences all number
    158
    35
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    30 / 327 (9.17%)
    20 / 329 (6.08%)
         occurrences all number
    55
    25
    back pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    38 / 327 (11.62%)
    39 / 329 (11.85%)
         occurrences all number
    48
    47
    myalgia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    36 / 327 (11.01%)
    32 / 329 (9.73%)
         occurrences all number
    64
    44
    pain in extremity
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    20 / 327 (6.12%)
    10 / 329 (3.04%)
         occurrences all number
    22
    10
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    23 / 327 (7.03%)
    19 / 329 (5.78%)
         occurrences all number
    34
    24
    urinary tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    18 / 327 (5.50%)
    11 / 329 (3.34%)
         occurrences all number
    22
    11
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    133 / 327 (40.67%)
    105 / 329 (31.91%)
         occurrences all number
    230
    172
    hypoalbuminaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    30 / 327 (9.17%)
    13 / 329 (3.95%)
         occurrences all number
    46
    16
    hyponatraemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    17 / 327 (5.20%)
    9 / 329 (2.74%)
         occurrences all number
    23
    13

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2010
    Overall changes from version 1.1. included clarification of inclusion criteria 2, 4, 6, and 10 and clarifying the frequency of radiographic assessments and IDMC evaluations of safety data. Other additions centered on updates guidelines for ramucirumab administration regarding dose adjustments related to changes in body weight; paclitaxel administration; pharmacodynamic assessments; the management of proteinuria; and the removal of participants from ramucirumab/placebo in the instance of venous thrombotic events. (Safety Evaluations) was updated to reflect new Sponsor standards for the reporting of AEs and SAEs. (Treatment Requirements and Delays) was restructured and tables were added in order to provide additional clarification. Language was added regarding the chronic use of NSAIDs as well as additional information about planned subgroup analysis of the primary endpoint.
    08 Oct 2012
    Overall changes from version 2.0 included clarification of coagulation parameters in the inclusion/exclusion criteria; infusion times for study treatment; ramucirumab dose based on patient’s body weight; complaint handling; and dose modifications of investigational drug in response to Grade 3 and Grade 4 AEs. Other additions included the additional information regarding CHF, impaired wound healing, liver injury/liver failure, and RPLS as AEs of concern; definitions of “study completion” and “extension period”; storage times for PK, pharmacodynamics, and immunogenicity blood samples; and ramucirumab discontinuation criteria related to liver injury/liver failure and CHF. The definition for “end of trial”, premedication language, dose rationale, the timeframe of when survival follow-up would continue through, and the timeframe for blood collection for clinical laboratory tests prior to Days 1, 8, and 15 were updated.

    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.
    One (1) participant was randomized to the placebo/paclitaxel group but received ramucirumab in error. For ITT population this participant was included in placebo/paclitaxel group and for the Safety population included in the ramucirumab group.
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