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    Clinical Trial Results:
    A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients with HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer

    Summary
    EudraCT number
    2008-001727-65
    Trial protocol
    ES   DE   BE   CZ   SK   PL   GB   GR   IE  
    Global end of trial date
    19 Nov 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    11 Mar 2022
    First version publication date
    20 Nov 2021
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    New data added to full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    I4T-IE-JVBC
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00703326
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Number: 13892
    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
    19 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to compare the progression-free survival (PFS) of the drug combination ramucirumab plus docetaxel to placebo plus docetaxel in previously untreated participants with human epidermal growth factor receptor 2 (HER2)-negative, unresectable, locally-recurrent or metastatic breast cancer.
    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 Aug 2008
    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
    Australia: 49
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Canada: 129
    Country: Number of subjects enrolled
    Egypt: 12
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Country: Number of subjects enrolled
    Lebanon: 38
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    Peru: 16
    Country: Number of subjects enrolled
    Russian Federation: 309
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    South Africa: 63
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Belgium: 68
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 182
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    1144
    EEA total number of subjects
    305
    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)
    954
    From 65 to 84 years
    190
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Not Applicable

    Pre-assignment
    Screening details
    Participants who were alive and completed the follow-up period or who died were considered to have completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ramucirumab (IMC-1121B) + Docetaxel
    Arm description
    Ramucirumab (IMC-1121B) is administered at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Ramucirumab (IMC-1121B)
    Investigational medicinal product code
    Other name
    IMC-1121B,LY3009806
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ramucirumab (IMC-1121B) is administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Arm title
    Placebo + Docetaxel
    Arm description
    Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.
    Arm type
    Placebo

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Started
    759
    385
    Received at least 1 dose of study drug
    752
    382
    Completed
    657
    347
    Not completed
    102
    38
         Consent withdrawn by subject
    54
    20
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    47
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ramucirumab (IMC-1121B) + Docetaxel
    Reporting group description
    Ramucirumab (IMC-1121B) is administered at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Reporting group title
    Placebo + Docetaxel
    Reporting group description
    Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Reporting group values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel Total
    Number of subjects
    759 385 1144
    Age categorical
    Units: Subjects
    Age continuous
    Intent-to-Treat (ITT) Population: All randomized participants.
    Units: years
        arithmetic mean (standard deviation)
    53.9 ± 10.5 54.2 ± 10.0 -
    Gender categorical
    Intent-to-Treat (ITT) Population: All randomized participants.
    Units: Subjects
        Female
    759 385 1144
        Male
    0 0 0
    Ethnicity (NIH/OMB)
    Intent-to-Treat (ITT) Population: All randomized participants.
    Units: Subjects
        Hispanic or Latino
    69 42 111
        Not Hispanic or Latino
    690 343 1033
        Unknown or Not Reported
    0 0 0
    Region of Enrollment
    Units: Subjects
        Serbia
    0 2 2
        United States
    58 21 79
        Taiwan
    4 2 6
        Slovakia
    2 2 4
        Spain
    118 64 182
        Lebanon
    24 14 38
        Ireland
    8 2 10
        Russian Federation
    210 99 309
        Israel
    16 7 23
        United Kingdom
    21 10 31
        Egypt
    9 3 12
        Czech Republic
    4 3 7
        Canada
    83 46 129
        Poland
    12 5 17
        Belgium
    48 20 68
        Brazil
    30 20 50
        Peru
    12 4 16
        Australia
    28 21 49
        South Africa
    41 22 63
        Germany
    12 5 17
        New Zealand
    5 6 11
        South Korea
    14 7 21
    Race
    Intent-to-Treat (ITT) Population: All randomized participants.
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    31 20 51
        Native Hawaiian or Other Pacific Islander
    2 0 2
        Black or African American
    27 14 41
        White
    676 341 1017
        Other
    22 9 31

    End points

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    End points reporting groups
    Reporting group title
    Ramucirumab (IMC-1121B) + Docetaxel
    Reporting group description
    Ramucirumab (IMC-1121B) is administered at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Reporting group title
    Placebo + Docetaxel
    Reporting group description
    Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Primary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS defined as time from randomization until the first evidence of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause; by Investigator assessment. Progressive disease (PD) defined as at least a 20% increase in sum of longest diameter of target lesions taking as reference the smallest sum longest diameter since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who neither progressed nor died were censored the day of their last radiographic tumor assessment if available or date of randomization if no post initiation radiographic assessment was available. If death or PD occurred after ≥2 missing radiographic visits, censoring occurred at date of last radiographic visit prior to the missed visits.The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression. Censored participants: ramucirumab + docetaxel=94.
    End point type
    Primary
    End point timeframe
    Randomization to disease progression or death or until data cutoff of 31 Mar 2013 (up to 56 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    759 [1]
    385 [2]
    Units: months
        median (confidence interval 95%)
    9.5 (8.3 to 9.8)
    8.2 (7.1 to 8.5)
    Notes
    [1] - Intent-to-Treat (ITT) Population: All randomized participants.
    [2] - Intent-to-Treat (ITT) Population: All randomized participants.
    Statistical analysis title
    Progression-Free Survival (PFS)
    Statistical analysis description
    Hazard ratio (HR) with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the Interactive Web Response System (IWRS) stratification factors.
    Comparison groups
    Ramucirumab (IMC-1121B) + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1144
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.077 [4]
    Method
    Stratified Log Rank (SLR)
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.01
    Notes
    [3] - Analysis type: Superiority or Other (legacy)
    [4] - SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the duration from randomization to death from any cause. Participants who were alive at data cut-off for the OS analysis or lost to follow-up were censored on the last date the participant was known to be alive. Censored participants: ramucirumab + docetaxel=267, placebo + docetaxel=121.
    End point type
    Secondary
    End point timeframe
    Randomization to death or until data cutoff of 29-May-2015 (up to 82 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    759 [5]
    385 [6]
    Units: months
        median (confidence interval 95%)
    30.3 (27.5 to 33.5)
    28.7 (25.6 to 32.3)
    Notes
    [5] - Intent-to-Treat (ITT) Population: All randomized participants.
    [6] - Intent-to-Treat (ITT) Population: All randomized participants.
    Statistical analysis title
    Overall Survival (OS)
    Statistical analysis description
    SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions. HR with 95% confidence interval (CI) was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    Comparison groups
    Ramucirumab (IMC-1121B) + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1144
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.487 [8]
    Method
    Stratified Log Rank (SLR)
    Parameter type
    Hazard ratio (HR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.1
    Notes
    [7] - Superiority or Other (legacy)
    [8] - The gate-keeping strategy used to control overall type 1 error 0.05 (2-sided) or 0.025 (1-sided) to analyze progression-free survival (PFS) and OS. At final PFS analysis only if primary PFS test was significant would analysis of OS be inferential.

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    TTP was defined as time from the date of randomization to first documented date of disease progression using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference smallest sum LD since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). Participants who did not progress were censored at the last radiographic tumor assessment. If no post-baseline assessment was available censoring occurred at the date of randomization. If PD occurred after 2 or more missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits. The symptomatic/clinical disease progression (deterioration) without documented radiologic progression did not constitute progression. Censored participants: ramucirumab + docetaxel=263, placebo + docetaxel=104.
    End point type
    Secondary
    End point timeframe
    Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 56 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    759 [9]
    385 [10]
    Units: months
        median (confidence interval 95%)
    11.4 (10.7 to 13.3)
    9.7 (8.2 to 10.9)
    Notes
    [9] - Intent-to-Treat (ITT) Population: All randomized participants.
    [10] - Intent-to-Treat (ITT) Population: All randomized participants.
    Statistical analysis title
    Time to Progression (TTP)
    Statistical analysis description
    HR with 95% CI was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    Comparison groups
    Ramucirumab (IMC-1121B) + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    1144
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.033 [12]
    Method
    Stratified Log Rank (SLR)
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.99
    Notes
    [11] - Superiority or Other (legacy)
    [12] - SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.

    Secondary: Percentage of Participants with Complete Response (CR) or Partial Response (PR) (Objective Response Rate)

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    End point title
    Percentage of Participants with Complete Response (CR) or Partial Response (PR) (Objective Response Rate)
    End point description
    Objective response rate (ORR) was defined as the percentage of randomized participants achieving a best confirmed overall response of CR or PR using Response Evaluation Criteria in Solid Tumors (RECIST v1.0), based on the achievement of both measurement and confirmation criteria; by Investigator assessment. CR was defined as the disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions, taking as reference the baseline sum LD and no progression in non-target lesions.
    End point type
    Secondary
    End point timeframe
    Randomization to disease progression or until data cutoff of 31-Mar-2013 (up to 56 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    759 [13]
    385 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    44.7 (41.1 to 48.3)
    37.9 (33.1 to 43.0)
    Notes
    [13] - Intent-to-Treat (ITT) Population: All randomized participants.
    [14] - Intent-to-Treat (ITT) Population: All randomized participants.
    Statistical analysis title
    Objective Response Rate
    Statistical analysis description
    Stratified odds ratio was calculated considering the IWRS stratification factors.
    Comparison groups
    Placebo + Docetaxel v Ramucirumab (IMC-1121B) + Docetaxel
    Number of subjects included in analysis
    1144
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.027 [16]
    Method
    Stratified Cochran-Mantel-Haenszel(SCMH)
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    1.71
    Notes
    [15] - Superiority or Other (legacy)
    [16] - SCMH used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of complete response (CR) or partial response (PR) measured from time criteria were first met for CR or PR until first date of progressive disease (PD) or death from any cause defined using RECIST 1.0; by Investigator assessment.CR defined as disappearance of all target and non-target lesions.PR defined as ≥30% decrease in sum of LD of target lesions and no progression in non-target lesions.PD defined as ≥20% increase in LD sum of target lesions taking as reference the smallest sum LD since baseline,progression in non-target lesions or the appearance of ≥1 new lesion(s).Participants who did not relapse or die censored at day of last radiographic tumor assessment.If death or PD was after ≥2 missing radiographic visits, censoring was at date of last radiographic visit prior to missed visits. Symptomatic/clinical disease progression without documented radiologic progression did not constitute progression. Censored participants: ramucirumab + docetaxel=80, placebo + docetaxel=28.
    End point type
    Secondary
    End point timeframe
    Date of first CR or PR to PD or death or until data cutoff date of 31-Mar-2013 (up to 56 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    339 [17]
    146 [18]
    Units: months
        median (confidence interval 95%)
    8.4 (8.0 to 9.7)
    8.1 (6.8 to 8.9)
    Notes
    [17] - A subset of the Intent-to-Treat (ITT) Population: all randomized participants with CR or PR.
    [18] - A subset of the Intent-to-Treat (ITT) Population: all randomized participants with CR or PR.
    Statistical analysis title
    Duration of Response
    Statistical analysis description
    HR with 95% CI was estimated using a stratified Cox proportional hazards regression model using the IWRS stratification factors.
    Comparison groups
    Ramucirumab (IMC-1121B) + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    P-value
    = 0.15 [20]
    Method
    Stratified Log Rank (SLR)
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.06
    Notes
    [19] - Superiority or Other (legacy)
    [20] - SLR used Interactive Web Response System (IWRS) factors: prior taxane therapy, visceral metastasis, hormone receptor status and geographical regions.

    Secondary: Total Functional Assessment of Cancer Therapy-Breast (FACT-B): Change From Baseline to End of Therapy

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    End point title
    Total Functional Assessment of Cancer Therapy-Breast (FACT-B): Change From Baseline to End of Therapy
    End point description
    FACT-B measures the following domains of health-related quality of life (HR-QoL): physical well-being (PWB), social/family well-being (SFWB), emotional well-being (EWB), functional well-being (FWB), and additional concerns of breast cancer subscale (BCS) each with 6 or more items developed to measure problems specific to breast cancer symptoms plus additional items related to global QoL. Participants (pts) respond to each of the 36 questions on a 5-point scale from 0 (not at all) to 4 (very much) with a total scores range of 0-144. Higher scores indicate fewer symptoms and better HR-QoL.
    End point type
    Secondary
    End point timeframe
    Baseline, End of Therapy or until data cutoff of 31-Mar-2013 (up to 56 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    494 [21]
    251 [22]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -6.8 ± 17.3
    -7.0 ± 16.8
    Notes
    [21] - A subset of ITT Population: all randomized pts with a valid baseline and end of therapy assesments.
    [22] - A subset of ITT Population: all randomized pts with a valid baseline and end of therapy assesments.
    Statistical analysis title
    FACT-B: Change From Baseline to End of Therapy
    Comparison groups
    Ramucirumab (IMC-1121B) + Docetaxel v Placebo + Docetaxel
    Number of subjects included in analysis
    745
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.539 [24]
    Method
    ANCOVA
    Confidence interval
    Notes
    [23] - Superiority or Other (legacy)
    [24] - P-value is for end of therapy. Analysis of covariance (ANCOVA) adjusted for baseline score was used to compare the 2 treatment arms.

    Secondary: Number of Participants with Adverse Events

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    End point title
    Number of Participants with Adverse Events
    End point description
    Clinically significant events were defined as serious adverse events (SAE) and other treatment-emergent non-serious adverse events (NSAE). A summary of SAEs and other NSAEs is located in the Reported Adverse Event module.
    End point type
    Secondary
    End point timeframe
    First dose to study completion (up to 12.3 years)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    752 [25]
    382 [26]
    Units: participants
    number (not applicable)
        Participants with SAEs
    286
    117
        Participants with NSAEs
    738
    373
    Notes
    [25] - All randomized participants who received at least 1 dose of study drug.
    [26] - All randomized participants who received at least 1 dose of study drug.
    No statistical analyses for this end point

    Secondary: Immunogenicity: Percentage of Participants With Treatment Emergent Anti-Ramucirumab Antibodies Until Primary Data Cutoff of 31-Mar-2013

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    End point title
    Immunogenicity: Percentage of Participants With Treatment Emergent Anti-Ramucirumab Antibodies Until Primary Data Cutoff of 31-Mar-2013
    End point description
    Percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals. Analysis population included all randomized participants who received at least 1 dose of study drug with anti-IMC-1121B antibodies samples collected during the study.
    End point type
    Secondary
    End point timeframe
    Baseline, prior to cycle 3 infusion, prior to cycle 5 infusion, onset of infusion reaction, resolution of reaction and 30 days following the event up to 56 months
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    715
    360
    Units: percentage of participants
        number (not applicable)
    0.8
    0.8
    No statistical analyses for this end point

    Secondary: Immunogenicity: Percentage of Participants Available After 31-Mar-2013 With Treatment Emergent Anti-Ramucirumab Antibodies Until Data Cutoff From 01-Apr-2013 to 08-Sep-2016

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    End point title
    Immunogenicity: Percentage of Participants Available After 31-Mar-2013 With Treatment Emergent Anti-Ramucirumab Antibodies Until Data Cutoff From 01-Apr-2013 to 08-Sep-2016
    End point description
    Percentage of participants with treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies during the study. Participants were considered positive for anti-ramucirumab (IMC-1121B) antibodies if they exhibited a post-treatment antibody level that exceeded the positive upper cut point determined from the anti-ramucirumab (IMC-1121B) level seen in healthy untreated individuals. Analysis population included all follow-up participants (additional participants who were available after primary data cut off 31-Mar-13) who received at least 1 dose of study drug with anti-IMC-1121B antibodies samples collected during the study.
    End point type
    Secondary
    End point timeframe
    Follow-up from 01-Apr-2013 to 08-Sep-2016 (Up to 56 -97 months)
    End point values
    Ramucirumab (IMC-1121B) + Docetaxel Placebo + Docetaxel
    Number of subjects analysed
    35
    22
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose to study completion (up to 12.3 years)
    Adverse event reporting additional description
    All randomized participants who received at least 1 dose of study drug.Disease progression without clinical manifestation or death related to progressive disease (PD) was not to be reported as an AE. However, all deaths within 30 days of last dose reported as SAE, regardless of causality. PD itself reported as an SAE,if any of the SAE criteria met.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo + Docetaxel
    Reporting group description
    Placebo comparator for ramucirumab (IMC-1121B) administered at a dose of 10 mg/kg as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Reporting group title
    Ramucirumab (IMC-1121B) + Docetaxel
    Reporting group description
    Ramucirumab (IMC-1121B) is administered at a dose of 10 milligrams per kilogram (mg/kg) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle. Docetaxel is administered at a dose of 75 milligrams per square meter (mg/m²) as a 1-hour intravenous infusion on Day 1 of each 21-day cycle.

    Serious adverse events
    Placebo + Docetaxel Ramucirumab (IMC-1121B) + Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    117 / 382 (30.63%)
    285 / 752 (37.90%)
         number of deaths (all causes)
    9
    30
         number of deaths resulting from adverse events
    1
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    acute myeloid leukaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    breast cancer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    colon cancer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemangioma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant ascites
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant neoplasm progression
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant pleural effusion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         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 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    metastases to meninges
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neoplasm progression
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    tumour embolism
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 382 (0.79%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    embolism
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypertension
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypertensive crisis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    jugular vein thrombosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lymphoedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subclavian vein thrombosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    therapy change
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    5 / 752 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chills
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    complication associated with device
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    disease progression
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 382 (1.05%)
    8 / 752 (1.06%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    extravasation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    face oedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    10 / 752 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    generalised oedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inflammation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infusion site thrombosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malaise
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mucosal inflammation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multiple organ dysfunction syndrome
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    oedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oedema peripheral
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    8 / 752 (1.06%)
         occurrences causally related to treatment / all
    1 / 2
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 382 (0.79%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    disability
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    menstruation irregular
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    uterine haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    uterine polyp
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vaginal haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute interstitial pneumonitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 382 (1.31%)
    5 / 752 (0.66%)
         occurrences causally related to treatment / all
    2 / 6
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epistaxis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infiltration
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 382 (1.57%)
    8 / 752 (1.06%)
         occurrences causally related to treatment / all
    2 / 7
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 382 (1.05%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    confusional state
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mood altered
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    thrombosis in device
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    blood calcium decreased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutrophil count decreased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ankle fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chemical burn of skin
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    expired product administered
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    facial bones fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hip fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    humerus fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ilium fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    incorrect dose administered
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infusion related reaction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    injury
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    medication error
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    9 / 752 (1.20%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    overdose
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 382 (1.31%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    1 / 11
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    procedural pneumothorax
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    product administration error
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    product dispensing error
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    product preparation issue
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radiation oesophagitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stoma site haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    suture rupture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    underdose
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    12 / 382 (3.14%)
    11 / 752 (1.46%)
         occurrences causally related to treatment / all
    0 / 24
    4 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound dehiscence
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wrong product administered
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    atrial fibrillation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial flutter
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac failure congestive
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    left ventricular dysfunction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericarditis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericarditis constrictive
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    right ventricular failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    supraventricular tachycardia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tachycardia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral ischaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebrovascular accident
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    demyelinating polyneuropathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    encephalopathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epilepsy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhagic stroke
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    headache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic encephalopathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hydrocephalus
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    loss of consciousness
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    migraine
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nervous system disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neuropathy peripheral
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    paraplegia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral motor neuropathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radiculopathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subarachnoid haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 382 (0.79%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    disseminated intravascular coagulation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    11 / 382 (2.88%)
    51 / 752 (6.78%)
         occurrences causally related to treatment / all
    12 / 12
    57 / 57
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    neutropenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    20 / 382 (5.24%)
    47 / 752 (6.25%)
         occurrences causally related to treatment / all
    23 / 23
    52 / 52
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    dacryostenosis acquired
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    panophthalmitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    papilloedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    visual acuity reduced
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal fistula
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (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 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colitis ischaemic
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    9 / 752 (1.20%)
         occurrences causally related to treatment / all
    2 / 2
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diverticular perforation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenitis haemorrhagic
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enterocolitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    faecaloma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric ulcer perforation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhoids
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus paralytic
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal pseudo-obstruction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    large intestinal ulcer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    large intestine perforation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mouth haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    5 / 752 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophagitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    retroperitoneal fibrosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    9 / 752 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholelithiasis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    hepatic function abnormal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    hepatic pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperbilirubinaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    liver disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    dermatitis allergic
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    erythema nodosum
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lichen sclerosus
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rash
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin ulcer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subcutaneous emphysema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    5 / 752 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    dysuria
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    proteinuria
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal impairment
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ureteric obstruction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bone pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    muscular weakness
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    musculoskeletal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myalgia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myositis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteonecrosis of jaw
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain in extremity
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pathological fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    abdominal infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal wall abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abscess intestinal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abscess limb
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abscess soft tissue
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    catheter site infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    8 / 752 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    clostridium difficile colitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    clostridium difficile infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diverticulitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis viral
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lymphangitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mastitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mucosal infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenic infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    9 / 382 (2.36%)
    19 / 752 (2.53%)
         occurrences causally related to treatment / all
    10 / 10
    18 / 19
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    neutropenic sepsis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oral herpes
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteomyelitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pelvic abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 382 (1.31%)
    15 / 752 (1.99%)
         occurrences causally related to treatment / all
    3 / 5
    8 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    pneumonia chlamydial
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    postoperative wound infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    retroperitoneal abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    sinusitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         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 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    streptococcal infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tonsillitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    tooth abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 382 (0.79%)
    6 / 752 (0.80%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vascular device infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    dehydration
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    7 / 752 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diabetes mellitus inadequate control
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fluid overload
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 752 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fluid retention
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 382 (0.26%)
    4 / 752 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 752 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 752 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lactic acidosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 752 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + Docetaxel Ramucirumab (IMC-1121B) + Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    373 / 382 (97.64%)
    737 / 752 (98.01%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    44 / 382 (11.52%)
    204 / 752 (27.13%)
         occurrences all number
    96
    405
    hot flush
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    21 / 382 (5.50%)
    34 / 752 (4.52%)
         occurrences all number
    22
    44
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    127 / 382 (33.25%)
    270 / 752 (35.90%)
         occurrences all number
    363
    549
    face oedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    27 / 382 (7.07%)
    73 / 752 (9.71%)
         occurrences all number
    30
    100
    fatigue
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    135 / 382 (35.34%)
    271 / 752 (36.04%)
         occurrences all number
    240
    481
    influenza like illness
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    29 / 382 (7.59%)
    39 / 752 (5.19%)
         occurrences all number
    40
    48
    non-cardiac chest pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    19 / 382 (4.97%)
    39 / 752 (5.19%)
         occurrences all number
    21
    43
    oedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    18 / 382 (4.71%)
    43 / 752 (5.72%)
         occurrences all number
    26
    48
    oedema peripheral
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    101 / 382 (26.44%)
    181 / 752 (24.07%)
         occurrences all number
    140
    274
    pyrexia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    44 / 382 (11.52%)
    110 / 752 (14.63%)
         occurrences all number
    65
    168
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    69 / 382 (18.06%)
    127 / 752 (16.89%)
         occurrences all number
    89
    179
    dyspnoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    75 / 382 (19.63%)
    163 / 752 (21.68%)
         occurrences all number
    90
    225
    epistaxis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    64 / 382 (16.75%)
    300 / 752 (39.89%)
         occurrences all number
    149
    817
    oropharyngeal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    27 / 382 (7.07%)
    65 / 752 (8.64%)
         occurrences all number
    36
    96
    pleural effusion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    28 / 382 (7.33%)
    69 / 752 (9.18%)
         occurrences all number
    29
    74
    rhinorrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    19 / 382 (4.97%)
    56 / 752 (7.45%)
         occurrences all number
    23
    82
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    27 / 382 (7.07%)
    49 / 752 (6.52%)
         occurrences all number
    27
    65
    insomnia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    33 / 382 (8.64%)
    99 / 752 (13.16%)
         occurrences all number
    39
    127
    Investigations
    weight increased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    92 / 382 (24.08%)
    123 / 752 (16.36%)
         occurrences all number
    105
    152
    weight decreased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    41 / 382 (10.73%)
    173 / 752 (23.01%)
         occurrences all number
    50
    209
    Injury, poisoning and procedural complications
    infusion related reaction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    24 / 382 (6.28%)
    41 / 752 (5.45%)
         occurrences all number
    43
    56
    Cardiac disorders
    tachycardia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    23 / 382 (6.02%)
    50 / 752 (6.65%)
         occurrences all number
    36
    70
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    36 / 382 (9.42%)
    64 / 752 (8.51%)
         occurrences all number
    45
    88
    dysgeusia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    32 / 382 (8.38%)
    68 / 752 (9.04%)
         occurrences all number
    66
    120
    headache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    70 / 382 (18.32%)
    171 / 752 (22.74%)
         occurrences all number
    98
    306
    neuropathy peripheral
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    64 / 382 (16.75%)
    101 / 752 (13.43%)
         occurrences all number
    78
    124
    paraesthesia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    31 / 382 (8.12%)
    47 / 752 (6.25%)
         occurrences all number
    40
    59
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    73 / 382 (19.11%)
    136 / 752 (18.09%)
         occurrences all number
    90
    193
    taste disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    58 / 382 (15.18%)
    105 / 752 (13.96%)
         occurrences all number
    89
    156
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    28 / 382 (7.33%)
    77 / 752 (10.24%)
         occurrences all number
    39
    108
    neutropenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    41 / 382 (10.73%)
    96 / 752 (12.77%)
         occurrences all number
    56
    175
    Eye disorders
    lacrimation increased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    65 / 382 (17.02%)
    233 / 752 (30.98%)
         occurrences all number
    90
    337
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    42 / 382 (10.99%)
    95 / 752 (12.63%)
         occurrences all number
    59
    141
    abdominal pain upper
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    24 / 382 (6.28%)
    51 / 752 (6.78%)
         occurrences all number
    33
    71
    constipation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    74 / 382 (19.37%)
    157 / 752 (20.88%)
         occurrences all number
    116
    293
    diarrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    152 / 382 (39.79%)
    326 / 752 (43.35%)
         occurrences all number
    338
    751
    dry mouth
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    20 / 382 (5.24%)
    29 / 752 (3.86%)
         occurrences all number
    33
    54
    dyspepsia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    40 / 382 (10.47%)
    75 / 752 (9.97%)
         occurrences all number
    57
    110
    gingival bleeding
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 382 (0.52%)
    73 / 752 (9.71%)
         occurrences all number
    2
    144
    haemorrhoids
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    8 / 382 (2.09%)
    39 / 752 (5.19%)
         occurrences all number
    8
    50
    nausea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    156 / 382 (40.84%)
    278 / 752 (36.97%)
         occurrences all number
    343
    766
    stomatitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    118 / 382 (30.89%)
    380 / 752 (50.53%)
         occurrences all number
    215
    833
    vomiting
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    80 / 382 (20.94%)
    155 / 752 (20.61%)
         occurrences all number
    127
    288
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    279 / 382 (73.04%)
    535 / 752 (71.14%)
         occurrences all number
    287
    550
    dry skin
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    21 / 382 (5.50%)
    55 / 752 (7.31%)
         occurrences all number
    21
    60
    nail disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    105 / 382 (27.49%)
    231 / 752 (30.72%)
         occurrences all number
    114
    250
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    33 / 382 (8.64%)
    106 / 752 (14.10%)
         occurrences all number
    36
    157
    pruritus
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    21 / 382 (5.50%)
    41 / 752 (5.45%)
         occurrences all number
    23
    44
    rash
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    47 / 382 (12.30%)
    109 / 752 (14.49%)
         occurrences all number
    63
    143
    Renal and urinary disorders
    proteinuria
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 382 (1.31%)
    44 / 752 (5.85%)
         occurrences all number
    5
    75
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    82 / 382 (21.47%)
    173 / 752 (23.01%)
         occurrences all number
    167
    359
    back pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    54 / 382 (14.14%)
    114 / 752 (15.16%)
         occurrences all number
    74
    143
    bone pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    41 / 382 (10.73%)
    92 / 752 (12.23%)
         occurrences all number
    82
    192
    musculoskeletal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    18 / 382 (4.71%)
    51 / 752 (6.78%)
         occurrences all number
    32
    105
    myalgia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    89 / 382 (23.30%)
    153 / 752 (20.35%)
         occurrences all number
    209
    292
    pain in extremity
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    47 / 382 (12.30%)
    107 / 752 (14.23%)
         occurrences all number
    66
    195
    Infections and infestations
    conjunctivitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    17 / 382 (4.45%)
    38 / 752 (5.05%)
         occurrences all number
    25
    42
    nasopharyngitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    20 / 382 (5.24%)
    63 / 752 (8.38%)
         occurrences all number
    30
    79
    upper respiratory tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    21 / 382 (5.50%)
    39 / 752 (5.19%)
         occurrences all number
    29
    48
    urinary tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    28 / 382 (7.33%)
    71 / 752 (9.44%)
         occurrences all number
    32
    91
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    62 / 382 (16.23%)
    165 / 752 (21.94%)
         occurrences all number
    101
    293

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2008
    Important overall changes included additional instructions related infusion and shelf life of Ramucirumab, and instructions to report any Grade 3 or 4 AE as an ‘important medical event’ using the serious adverse event report (SAER) form.
    23 Apr 2009
    Important overall changes included new details on prohibited therapies, expanded to include hormonal therapy; additional instructions related to the preparation and administration of study drugs, and SAEs reporting.
    06 Dec 2010
    Important overall changes included the addition of an inclusion criterion to specify that participants that received prior biologic therapy in the metastatic setting were not eligible, changes to the interim analyses plan, with a reduction to one single analysis at 40% of the expected PFS events; updates to the unblinding procedures and reporting SAEs and other updates in different sections of the protocol, including pre-medications.
    23 Apr 2012
    Important overall changes included updates on the assessment of PFS and response-related endpoints, clarifications and details related to the OS analysis, additional instructions for the management of the reversible posterior leukoencephalopathy syndrome (RPLS) and other more administrative updates.

    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 participant assigned to placebo + docetaxel (doc) treatment and was given ramucirumab (ram) in Cycle 1. Considered ram + doc treatment arm for safety population, for ITT population the participant was analyzed according to assigned treatment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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