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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blinded Study of IMC-1121B and Best Supportive Care (BSC) Versus Placebo and BSC in the Treatment of Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Following Disease Progression on First-Line Platinum- or Fluoropyrimidine-Containing Combination Therapy

    Summary
    EudraCT number
    		 2008-005964-15
    Trial protocol
    		 IT   ES   CZ   MT   GB  
    Global end of trial date
    17 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Dec 2016
    First version publication date
    24 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13893
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00917384
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Alias: I4T-IE-JVBD , Trial Number: 13893
    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
    17 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to gather information about the use of an investigational drug called Ramucirumab in adenocarcinomas of the stomach or gastroesophageal junction.
    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
    21 Aug 2009
    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
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 4
    Country: Number of subjects enrolled
    Brazil: 38
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czech Republic: 37
    Country: Number of subjects enrolled
    Egypt: 1
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Guatemala: 8
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Indonesia: 3
    Country: Number of subjects enrolled
    India: 24
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Lebanon: 1
    Country: Number of subjects enrolled
    Malta: 5
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 43
    Country: Number of subjects enrolled
    South Africa: 1
    Worldwide total number of subjects
    355
    EEA total number of subjects
    146
    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)
    224
    From 65 to 84 years
    129
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants who completed were those who died due to any cause or were alive and on study at conclusion but off treatment.

    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, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IMC-1121B (ramucirumab )
    Arm description
    		 Participants received IMC-1121B (ramucirumab), administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), plus best supportive care (BSC) as determined appropriate by the investigator(s). Treatment continued until there was evidence of progressive disease (PD), the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    IMC-1121B, LY3009806
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received IMC-1121B (ramucirumab), administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), plus best supportive care (BSC).

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo by intravenous infusion every 2 weeks plus BSC as determined appropriate by the investigator(s). Because investigators and ancillary medical personnel were blinded as to assignment to active therapy versus placebo, the volume of placebo administered was calculated as if it were active product with a dose of 8 mg/kg. Treatment continued until there was evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received placebo by intravenous infusion every 2 weeks plus BSC.

    Number of subjects in period 1
    		IMC-1121B (ramucirumab ) Placebo
    Started
    238
    117
    Received at least 1 dose of study drug
    236
    115
    Completed
    224
    113
    Not completed
    14
    4
         Consent withdrawn by subject
    10
    2
         Lost to follow-up
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IMC-1121B (ramucirumab )
    Reporting group description
    		 Participants received IMC-1121B (ramucirumab), administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), plus best supportive care (BSC) as determined appropriate by the investigator(s). Treatment continued until there was evidence of progressive disease (PD), the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo by intravenous infusion every 2 weeks plus BSC as determined appropriate by the investigator(s). Because investigators and ancillary medical personnel were blinded as to assignment to active therapy versus placebo, the volume of placebo administered was calculated as if it were active product with a dose of 8 mg/kg. Treatment continued until there was evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.

    Reporting group values
    		 IMC-1121B (ramucirumab ) Placebo Total
    Number of subjects
    		 238 117 355
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 154 70 224
        From 65-84 years
    		 83 46 129
        85 years and over
    		 1 1 2
    Gender, Male/Female
    Units: participants
        Female
    		 69 38 107
        Male
    		 169 79 248
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 41 19 60
        Not Hispanic or Latino
    		 197 98 295
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Argentina
    		 4 2 6
        Australia
    		 8 4 12
        Bosnia and Herzegovina
    		 1 3 4
        Brazil
    		 24 14 38
        Canada
    		 8 2 10
        Chile
    		 1 1 2
        Colombia
    		 2 1 3
        Czech Republic
    		 24 13 37
        Egypt
    		 1 0 1
        Spain
    		 12 4 16
        United Kingdom
    		 13 4 17
        Guatemala
    		 6 2 8
        Croatia
    		 7 0 7
        Indonesia
    		 2 1 3
        India
    		 16 8 24
        Italy
    		 23 11 34
        Korea, Republic of
    		 11 6 17
        Lebanon
    		 1 0 1
        Malta
    		 2 3 5
        New Zealand
    		 1 1 2
        Philippines
    		 1 1 2
        Poland
    		 9 4 13
        Romania
    		 13 4 17
        Russian Federation
    		 14 8 22
        Thailand
    		 1 0 1
        Turkey
    		 5 1 6
        Taiwan
    		 3 0 3
        United States
    		 25 18 43
        South Africa
    		 0 1 1
    Race
    Units: Subjects
        White
    		 181 91 272
        Asian
    		 39 17 56
        Black
    		 4 2 6
        Other
    		 14 7 21

    End points

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    End points reporting groups
    Reporting group title
    IMC-1121B (ramucirumab )
    Reporting group description
    		 Participants received IMC-1121B (ramucirumab), administered via intravenous infusion every 2 weeks at a dose of 8 milligrams/kilogram (mg/kg), plus best supportive care (BSC) as determined appropriate by the investigator(s). Treatment continued until there was evidence of progressive disease (PD), the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo by intravenous infusion every 2 weeks plus BSC as determined appropriate by the investigator(s). Because investigators and ancillary medical personnel were blinded as to assignment to active therapy versus placebo, the volume of placebo administered was calculated as if it were active product with a dose of 8 mg/kg. Treatment continued until there was evidence of PD, the development of unacceptable toxicity, protocol noncompliance, or withdrawal of consent.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the date of data cut-off or who were lost to follow-up were censored on the last date the participant was known to be alive
    End point type
    Primary
    End point timeframe
    Randomization up to 28 months post-randomization
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    238
    117
    Units: months
        median (confidence interval 95%)
    5.2 (4.4 to 5.7)
    3.8 (2.8 to 4.7)
    Statistical analysis title
    		 Overall Survival Statistical Analysis
    Comparison groups
    IMC-1121B (ramucirumab ) v Placebo
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0473 [1]
    Method
    		 Stratified Log-Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.776
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.603
         upper limit
    		 0.998
    Notes
    [1] - Stratified Log-Rank Test and HR stratified by randomization strata (weight loss over the prior 3 months, primary tumor site and geographical region).

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the time from date of randomization until date of objectively determined progressive disease (PD) or death due to any cause, whichever is first. Participants alive and without PD were censored at the time of last adequate objective tumor assessment (that is, response other than unevaluable).
    End point type
    Secondary
    End point timeframe
    Randomization up to 17 months
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    238
    117
    Units: months
        median (confidence interval 95%)
    2.1 (1.5 to 2.7)
    1.3 (1.3 to 1.4)
    Statistical analysis title
    		 Progression-Free Survival Statistical Analysis
    Comparison groups
    Placebo v IMC-1121B (ramucirumab )
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Stratified Log-Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.483
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.376
         upper limit
    		 0.62
    Notes
    [2] - Stratified Log-Rank Test and HR stratified by randomization strata (weight loss over the prior 3 months, primary tumor site and geographical region).

    Secondary: Percentage of Participants Who are Progression-Free at Week 12 (PFS Rate)

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    End point title
    		 Percentage of Participants Who are Progression-Free at Week 12 (PFS Rate)
    End point description
    The percentage of participants alive and progression-free 12 weeks after randomization. Progression-free survival (PFS) is defined as the time from the date of randomization until the date of objectively determined progressive disease (PD) or death due to any cause whichever comes first. Participants alive and without PD were censored at the time of the last adequate objective tumor assessment.
    End point type
    Secondary
    End point timeframe
    Week 12 post-randomization
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    238
    117
    Units: percentage of participants
        number (confidence interval 95%)
    40.1 (33.6 to 46.4)
    15.8 (9.7 to 23.3)
    Statistical analysis title
    		 PFS Rate Statistical Analysis
    Comparison groups
    Placebo v IMC-1121B (ramucirumab )
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal Approximation
    Parameter type
    		 Difference Between Arms
    Point estimate
    24.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.9
         upper limit
    		 33.6

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

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    End point title
    		 Percentage of Participants with Objective Response (Objective Response Rate [ORR])
    End point description
    ORR is equal to the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR). CR and PR were defined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR is defined as the disappearance of all target and non-target lesions, no appearance of new lesions and confirmed at the consecutive tumor assessment. PR is 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), no progression of non-target lesions, no appearance of new lesions and confirmed at a subsequent tumor assessment.
    End point type
    Secondary
    End point timeframe
    Randomization up to 17 months post-randomization
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    238
    117
    Units: percentage of participants
        number (confidence interval 95%)
    3.4 (1.5 to 6.5)
    2.6 (0.5 to 7.3)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR is the interval from date of initial documented response (complete response [CR] or partial response [PR]) to first documented date of disease progression (PD) or death as a result of any cause. CR and PR were defined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR is defined as the disappearance of all target and non-target lesions, no appearance of new lesions and confirmed at the consecutive tumor assessment. PR is 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), no progression of non-target lesions, no appearance of new lesions and confirmed at a subsequent tumor assessment. Participants who did not relapse or die were censored at the time of the last adequate objective tumor assessment.
    End point type
    Secondary
    End point timeframe
    Randomization up to 17 months post-randomization
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: number
        number (not applicable)
    Notes
    [3] - The number of all responders (participants with CR or PR) was too small for a meaningful analysis.
    [4] - The number of all responders (participants with CR or PR) was too small for a meaningful analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Quality of Life (QoL) as measured by the European Organisation for Research and Treatment of Cancer Questionnaire (EORTC-QLQ-C30)

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    End point title
    		 Change from Baseline in Quality of Life (QoL) as measured by the European Organisation for Research and Treatment of Cancer Questionnaire (EORTC-QLQ-C30)
    End point description
    EORTC QLQ-C30 v3.0 is a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. Best change from baseline results determined by Least Square (LS) mean estimated with randomization stratification factors and baseline value as continuous covariate.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 10 (18 weeks [1 cycle=2 weeks])
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    114 [5]
    26 [6]
    Units: units on a scale
    least squares mean (standard error)
        Global Health Status/QoL
    2.42 ( 2.99 )
    0.8 ( 4.48 )
        Physical Functioning
    -6.26 ( 3.2 )
    -12.01 ( 4.82 )
        Role Functioning
    -4.32 ( 4.65 )
    -11.79 ( 6.99 )
        Emotional Functioning
    -1.61 ( 3.29 )
    -6.51 ( 4.92 )
        Cognitive Functioning
    -4.26 ( 2.63 )
    -10.94 ( 3.94 )
        Social Functioning
    -1.98 ( 3.9 )
    -1.37 ( 5.86 )
        Fatigue
    3.16 ( 3.43 )
    6.88 ( 5.16 )
        Nausea and Vomiting
    1.77 ( 2.86 )
    2.88 ( 4.32 )
        Pain
    0.13 ( 3.61 )
    3.85 ( 5.42 )
        Dyspnea
    -2.61 ( 3.35 )
    3.51 ( 5.08 )
        Insomnia
    -7.47 ( 4.19 )
    -3.95 ( 6.28 )
        Appetite Loss
    -1.01 ( 4.6 )
    7.16 ( 6.91 )
        Constipation
    0.09 ( 3.79 )
    7.94 ( 5.69 )
        Diarrhea
    -3.97 ( 1.64 )
    -5.49 ( 2.46 )
        Financial Difficulties
    -12.86 ( 3.78 )
    -2.39 ( 5.68 )
    Notes
    [5] - All randomized participants with EORTC QLQ-C30 values at baseline and up to 18 weeks post-baseline.
    [6] - All randomized participants with EORTC QLQ-C30 values at baseline and up to 18 weeks post-baseline.
    No statistical analyses for this end point

    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 all other NSAEs is located in the Reported Adverse Event module.
    End point type
    Secondary
    End point timeframe
    Randomization up to 18 months
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    236 [7]
    115 [8]
    Units: participants
    number (not applicable)
        Participants with SAE
    112
    51
        Participants with ≥ 1 treatment emergent NSAE
    213
    91
    Notes
    [7] - All randomized participants who received at least 1 dose of study drug.
    [8] - All randomized participants who received at least 1 dose of study drug.
    No statistical analyses for this end point

    Secondary: Maximum concentration (Cmax) of IMC-1121B

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    End point title
    		 Maximum concentration (Cmax) of IMC-1121B
    End point description
    Cmax was not analyzed as only pre-dose samples were collected.
    End point type
    Secondary
    End point timeframe
    6 weeks post-randomization
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: number
        number (not applicable)
    Notes
    [9] - Cmax was not analyzed as only pre-dose samples were collected.
    [10] - Cmax was not analyzed as only pre-dose samples were collected.
    No statistical analyses for this end point

    Secondary: Number of Participants who developed Antibodies against IMC-1121B

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    End point title
    		 Number of Participants who developed Antibodies against IMC-1121B
    End point description
    The number of participants who developed treatment emergent antibody responses to IMC-1121B after baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 Weeks
    End point values
    		 IMC-1121B (ramucirumab ) Placebo
    Number of subjects analysed
    207 [11]
    106 [12]
    Units: participants
        number (not applicable)
    6
    1
    Notes
    [11] - Subset of the Safety Population: Received at least 1 dose of study drug and had immunogenicity data.
    [12] - Subset of the Safety Population: Received at least 1 dose of study drug and had immunogenicity data.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    I4T-IE-JVBD
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo + BSC
    Reporting group description
    		 -

    Reporting group title
    Ramucirumab 8mg/kg + BSC
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo + BSC Ramucirumab 8mg/kg + BSC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 115 (44.35%)
    112 / 236 (47.46%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    gastric cancer recurrent
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric cancer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    malignant pleural effusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant neoplasm progression
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 115 (2.61%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    metastases to central nervous system
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to spine
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 115 (2.61%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    embolism
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (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 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypovolaemic shock
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    orthostatic hypotension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    jejunostomy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal stent insertion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 115 (3.48%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    5 / 236 (2.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    device dislocation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    disease progression
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 115 (6.96%)
    10 / 236 (4.24%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 10
         deaths causally related to treatment / all
    0 / 6
    1 / 8
    extravasation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    mucosal inflammation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    6 / 236 (2.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    systemic inflammatory response syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    vaginal laceration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [1]
    0 / 38 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    dyspnoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    pleural effusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary oedema
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mental status changes
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood bilirubin increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    weight decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    accidental overdose
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    drug dispensing error
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    feeding tube complication
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    incorrect dose administered
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    medication error
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    7 / 236 (2.97%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multiple injuries
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    overdose
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    underdose
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    cardiac arrest
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    myocardial infarction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    sinus bradycardia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral ischaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebrovascular accident
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coma
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperammonaemic encephalopathy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    11 / 236 (4.66%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    disseminated intravascular coagulation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancytopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain upper
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 115 (2.61%)
    10 / 236 (4.24%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 115 (2.61%)
    6 / 236 (2.54%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colonic obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspepsia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 115 (2.61%)
    6 / 236 (2.54%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematemesis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    gastric haemorrhage
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    ileus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    5 / 236 (2.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    intestinal perforation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    large intestine perforation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    obstruction gastric
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal fistula
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal stenosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    proctalgia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 115 (4.35%)
    7 / 236 (2.97%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cholecystitis acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholestasis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hyperbilirubinaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    jaundice cholestatic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    liver disorder
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    nephrolithiasis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ureteric obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         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 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ureteric perforation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    inappropriate antidiuretic hormone secretion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         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
    back pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    flank pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    abscess
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bacteraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    biliary sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cystitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    liver abscess
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lobar pneumonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    lung infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    peritonitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    septic shock
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 115 (2.61%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hyperkalaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoalbuminaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoglycaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 115 (1.74%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypophagia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoproteinaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of participants adjusted for gender specific AE event.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + BSC Ramucirumab 8mg/kg + BSC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 115 (79.13%)
    213 / 236 (90.25%)
    Investigations
    weight decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    11 / 115 (9.57%)
    26 / 236 (11.02%)
         occurrences all number
    13
    34
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    9 / 115 (7.83%)
    35 / 236 (14.83%)
         occurrences all number
    31
    125
    hypotension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 115 (5.22%)
    5 / 236 (2.12%)
         occurrences all number
    7
    6
    Nervous system disorders
    dysgeusia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 115 (5.22%)
    7 / 236 (2.97%)
         occurrences all number
    9
    7
    dizziness
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 115 (5.22%)
    4 / 236 (1.69%)
         occurrences all number
    7
    6
    headache
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 115 (3.48%)
    21 / 236 (8.90%)
         occurrences all number
    4
    28
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    16 / 115 (13.91%)
    33 / 236 (13.98%)
         occurrences all number
    22
    41
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    16 / 115 (13.91%)
    30 / 236 (12.71%)
         occurrences all number
    19
    60
    fatigue
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    28 / 115 (24.35%)
    58 / 236 (24.58%)
         occurrences all number
    52
    90
    oedema peripheral
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    10 / 115 (8.70%)
    21 / 236 (8.90%)
         occurrences all number
    11
    27
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    26 / 115 (22.61%)
    40 / 236 (16.95%)
         occurrences all number
    36
    53
    abdominal pain upper
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 115 (4.35%)
    26 / 236 (11.02%)
         occurrences all number
    5
    35
    constipation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    24 / 115 (20.87%)
    37 / 236 (15.68%)
         occurrences all number
    38
    53
    diarrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    9 / 115 (7.83%)
    35 / 236 (14.83%)
         occurrences all number
    12
    64
    ascites
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 115 (6.96%)
    18 / 236 (7.63%)
         occurrences all number
    8
    23
    dyspepsia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    7 / 115 (6.09%)
    6 / 236 (2.54%)
         occurrences all number
    7
    8
    dysphagia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    11 / 115 (9.57%)
    23 / 236 (9.75%)
         occurrences all number
    22
    33
    nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    30 / 115 (26.09%)
    45 / 236 (19.07%)
         occurrences all number
    44
    62
    vomiting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    26 / 115 (22.61%)
    45 / 236 (19.07%)
         occurrences all number
    36
    70
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    9 / 115 (7.83%)
    19 / 236 (8.05%)
         occurrences all number
    9
    20
    epistaxis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 115 (0.87%)
    12 / 236 (5.08%)
         occurrences all number
    1
    15
    dyspnoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    15 / 115 (13.04%)
    21 / 236 (8.90%)
         occurrences all number
    23
    24
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 115 (6.96%)
    13 / 236 (5.51%)
         occurrences all number
    8
    14
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    11 / 115 (9.57%)
    18 / 236 (7.63%)
         occurrences all number
    22
    22
    pain in extremity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 115 (5.22%)
    8 / 236 (3.39%)
         occurrences all number
    11
    11
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    26 / 115 (22.61%)
    55 / 236 (23.31%)
         occurrences all number
    39
    90
    hypoalbuminaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 115 (5.22%)
    11 / 236 (4.66%)
         occurrences all number
    6
    15
    hypokalaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 115 (4.35%)
    13 / 236 (5.51%)
         occurrences all number
    5
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2009
    Version 4.0 - changes to Adverse Events (bleedings were added)
    20 Apr 2010
    Version 5.1 - included only minor changes/clarifications not affecting the conduct of the study / planned analyses.
    23 Nov 2010
    Version 6.0 - major changes - decrease in planned sample size; Study Duration and Extended Follow-Up/Survival ; Section on gastrointestinal perforation was added
    31 Oct 2011
    Version 7.0 - primary purpose was to increase the planned sample size to 348 patients from 315 patients; changed survival follow-up; create a clear definition of the end of the trial

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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