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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Capecitabine and Cisplatin With or Without Ramucirumab as First-line Therapy in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (RAINFALL)

    Summary
    EudraCT number
    		 2014-002240-40
    Trial protocol
    		 HU   DE   FI   NL   IT   ES   PL   BE   GB   CZ   DK  
    Global end of trial date
    14 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2021
    First version publication date
    15 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I4T-MC-JVCU
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02314117
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 15372
    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
    14 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the efficacy of ramucirumab, which is a targeted antibody, in combination with capecitabine and cisplatin compared to capecitabine and cisplatin alone in participants with stomach 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
    20 Jan 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Argentina: 43
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    United States: 73
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    Japan: 60
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Italy: 73
    Country: Number of subjects enrolled
    Mexico: 52
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Germany: 33
    Worldwide total number of subjects
    645
    EEA total number of subjects
    284
    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)
    405
    From 65 to 84 years
    238
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Available

    Pre-assignment
    Screening details
    		 Completers are defined as participants who died or those who were alive and off treatment when the study completed.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ramucirumab + Cisplatin + Capecitabine
    Arm description
    		 8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    Other name
    LY3009806,IMC-1121B,Cyramza
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally

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

    Investigational medicinal product name
    Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV

    Arm title
    		 Placebo + Cisplatin + Capecitabine
    Arm description
    		 Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally

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

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV

    Investigational medicinal product name
    Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV

    Number of subjects in period 1
    		Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Started
    326
    319
    Received at least one dose of study drug
    323
    315
    Completed
    314
    303
    Not completed
    12
    16
         Consent withdrawn by subject
    3
    2
         Lost to follow-up
    9
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ramucirumab + Cisplatin + Capecitabine
    Reporting group description
    		 8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.

    Reporting group title
    Placebo + Cisplatin + Capecitabine
    Reporting group description
    		 Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.

    Reporting group values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine Total
    Number of subjects
    		 326 319 645
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ( 11.6 ) 60.1 ( 11.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 112 104 216
        Male
    		 214 215 429
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 67 62 129
        Not Hispanic or Latino
    		 227 245 472
        Unknown or Not Reported
    		 32 12 44
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 12 11 23
        Asian
    		 38 31 69
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 2 3 5
        White
    		 256 264 520
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 17 10 27
    Region of Enrollment
    Units: Subjects
        Puerto Rico
    		 1 1 2
        Argentina
    		 21 22 43
        Hungary
    		 15 16 31
        United States
    		 42 31 73
        Czechia
    		 11 8 19
        Japan
    		 32 28 60
        United Kingdom
    		 20 22 42
        Russia
    		 25 25 50
        Spain
    		 10 13 23
        Canada
    		 10 6 16
        Netherlands
    		 4 7 11
        Belgium
    		 8 5 13
        Finland
    		 3 5 8
        Denmark
    		 12 3 15
        Poland
    		 8 10 18
        Italy
    		 28 45 73
        Mexico
    		 26 26 52
        Israel
    		 11 12 23
        France
    		 19 21 40
        Germany
    		 20 13 33

    End points

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    End points reporting groups
    Reporting group title
    Ramucirumab + Cisplatin + Capecitabine
    Reporting group description
    		 8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.

    Reporting group title
    Placebo + Cisplatin + Capecitabine
    Reporting group description
    		 Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day 5-FU IV on days 1 to 5 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 time was measured from the date of randomization to the date of radiographic(rgr) documentation of progression(by RECIST v.1.1) or the date of death due to any cause, whichever was earlier.If a participant did not have a complete baseline tumor assessment,then the PFS time was censored at the randomization date.If a participant was not known to have died or have rgr documented progression as of the data cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. If death or progressive disease(PD) occurred after 2 or more consecutive missing rgr visits,censoring occurred at the date of the last rgr visit prior to the missed visits.If death or PD occurred after postdiscontinuation(pdis) systemic anticancer therapy,censoring occurred at the date of last rgr visit prior to the start of pdis systemic anticancer therapy. PD was defined according to RECIST v.1.1.
    End point type
    Primary
    End point timeframe
    Randomization to Radiological Disease Progression or Death from Any Cause (Up to 26 Months) Analysis Population: First 508 randomized participants. Participants censored: Ramucirumab + Cisplatin + Capecitabine=87 and Placebo+Cisplatin+Capecitabine=62.
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    255
    253
    Units: months
        median (confidence interval 95%)
    5.72 (5.45 to 6.51)
    5.39 (4.47 to 5.72)
    Statistical analysis title
    		 Progression-free Survival (PFS)
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.753
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.607
         upper limit
    		 0.935

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was time from the date of randomization to the date of death from any cause. If the participant was alive at the cutoff for analysis (or was lost to follow-up), OS data were censored for analysis on the last date the participant was known to be alive. Analysis Population Description (APD): All randomized participants. Participants censored: Ramucirumab + Cisplatin + Capecitabine=87 and Placebo + Cisplatin + Capecitabine=88.
    End point type
    Secondary
    End point timeframe
    Randomization to Death from Any Cause (Up To 30 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326
    319
    Units: months
        median (confidence interval 95%)
    11.17 (9.92 to 11.93)
    10.74 (9.53 to 11.89)
    Statistical analysis title
    		 Overall Survival (OS)
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.962
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.801
         upper limit
    		 1.156

    Secondary: Progression- free Survival 2 (PFS2)

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    End point title
    		 Progression- free Survival 2 (PFS2)
    End point description
    PFS2 was defined as the time from the date of randomization to second disease progression (defined as objective radiological or symptomatic progression), or death of any cause, whichever occurs first. Participants alive and for whom a second disease progression has not been observed (including participants who did not receive any additional systemic anticancer treatments) were censored at the last time known to be alive and without second disease progression. The second progression refers to disease progression on or after additional systemic anticancer therapy, regardless if any earlier progression is observed or not(e.g. at the end of study treatment). It is assessed by investigator based on overall clinical evaluation, not limited to RECIST. APD: All randomized participants. Participants censored: Ramucirumab + Cisplatin + Capecitabine=74 and Placebo + Cisplatin + Capecitabine=74.
    End point type
    Secondary
    End point timeframe
    Randomization to Second Radiological or Symptomatic Disease Progression After the Start of Additional Systemic Anticancer Treatment or Death from Any Cause (Up To 26 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326
    319
    Units: months
        median (confidence interval 95%)
    10.18 (9.03 to 10.84)
    9.20 (8.34 to 9.99)
    Statistical analysis title
    		 Progression- free Survival 2 (PFS2)
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.926
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.774
         upper limit
    		 1.108

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

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    End point title
    		 Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])
    End point description
    Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1).Target lesions - CR: Disappearance of all lesions; any pathological lymph nodes must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum. PD: At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study (the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). Non target lesions – CR: Disappearance of all lesions and normalization of tumor marker levels; all lymph nodes must be non-pathological in size. Non-CR/Non-PD: Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels. PD: Unequivocal progression of existing lesions or the appearance of new lesion(s).ORR calculated as:(sum of the number of participants with PRs and CRs) divided by (number of evaluable participants) multiplied by 100. APD: All randomized participants.
    End point type
    Secondary
    End point timeframe
    Randomization to Disease Progression (Up To 26 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326
    319
    Units: percentage of participants
        number (confidence interval 95%)
    41.1 (35.8 to 46.4)
    36.4 (31.1 to 41.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate [DCR])

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    End point title
    		 Percentage of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate [DCR])
    End point description
    DCR was the percentage of participants with a best overall response of CR, PR, or SD as per Response using RECIST v1.1 criteria. Target lesions - CR: Disappearance of all lesions; any pathological lymph nodes must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum. Progressive Disease (PD): At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study (the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Non target lesions – CR: Disappearance of all lesions and normalization of tumor marker levels; all lymph nodes must be non-pathological in size. Non-CR/Non-PD: Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels. PD: Unequivocal progression of existing lesions or the appearance of new lesion(s).
    End point type
    Secondary
    End point timeframe
    Randomization to Disease Progression (Up To 26 Months) APD: All randomized participants.
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326
    319
    Units: percentage of participants
        number (confidence interval 95%)
    81.9 (77.7 to 86.1)
    76.5 (71.8 to 81.1)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    TTP was time from the date of randomization to the date of radiographic progression (according to RECIST v.1.1). If a participant died due to any reason without radiographic progression, TTP is censored at the last adequate tumor assessment. Target lesions: Progressive Disease (PD): At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study (the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). Non target lesions: PD: Unequivocal progression of existing lesions or the appearance of new lesion(s).
    End point type
    Secondary
    End point timeframe
    Randomization to Disease Progression (Up To 24 Months) APD: All randomized participants. Participants censored: Ramucirumab + Cisplatin + Capecitabine=149 and Placebo + Cisplatin + Capecitabine=111.
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326
    319
    Units: months
        median (confidence interval 95%)
    6.77 (5.88 to 7.66)
    5.78 (5.55 to 6.37)
    Statistical analysis title
    		 Time to Progression (TTP)
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.699
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.569
         upper limit
    		 0.859

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Participants achieved an objective response if they had a best overall response of CR or PR.Target lesions- CR:Disappearance of all lesions;any pathological lymph nodes must have reduction in short axis to <10 mm.PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum.PD: At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study(the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s).Non target lesions - CR: Disappearance of all lesions and normalization of tumour marker levels;all lymph nodes must be non-pathological in size. Non-CR/Non-PD:Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels.PD:Unequivocal progression of existing lesions or the appearance of new lesion(s).If a participant was not known to have died or have radiographically documented PD as of the data inclusion cutoff date,DOR was censored at the date of the last adequate tumor assessment.
    End point type
    Secondary
    End point timeframe
    Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 26 Months) All randomized participants.Censored:Ramucirumab+Cisplatin+Capecitabine=23 & Placebo +Cisplatin+Capecitabine=10
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    134
    116
    Units: months
        median (confidence interval 95%)
    5.72 (5.09 to 6.34)
    4.27 (3.88 to 4.90)
    Statistical analysis title
    		 Duration of Response (DoR)
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.499
         upper limit
    		 0.866

    Secondary: Time to Deterioration in Quality of Life (QoL) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Global Health Status/ QoL Scale

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    End point title
    		 Time to Deterioration in Quality of Life (QoL) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Global Health Status/ QoL Scale
    End point description
    Time to sustained deterioration was defined as time from randomization to first worsening in QoL with no subsequent non-worsened assessment. Worsening in global health status/QoL was defined as a decrease of ≥10 points on a 100-point scale. If a participant did not report worsening, time to sustained deterioration was censored at date of last non-worsened assessment. APD: All randomized participants. Participants censored: Ramucirumab + Cisplatin + Capecitabine=215 and Placebo + Cisplatin + Capecitabine=217.
    End point type
    Secondary
    End point timeframe
    Randomization, First worsening in QoL (Up To 26 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326
    319
    Units: months
        median (confidence interval 95%)
    9.00 (8.08 to 12.58)
    9.46 (6.74 to 11.99)
    Statistical analysis title
    		 Time to Deterioration in Quality of Life (QoL)
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.332

    Secondary: Change in Health Status on the EuroQol 5-Dimensions 5-Level Instrument (EQ-5D- 5L)

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    End point title
    		 Change in Health Status on the EuroQol 5-Dimensions 5-Level Instrument (EQ-5D- 5L)
    End point description
    The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Five dimensions of health status are each assessed with 5 response options and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status. Additionally, current health status was assessed on a visual analogue scale (VAS) ranging from 0 to 100 with a higher score representing better health status. APD: All randomized participants who provided data at baseline and cycle 6.
    End point type
    Secondary
    End point timeframe
    Randomization, 30 Days After Treatment Discontinuation (Up To 5 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    136
    125
    Units: units on a scale
    arithmetic mean (standard deviation)
        EQ-5D index
    -0.008 ( 0.148 )
    -0.010 ( 0.157 )
        EQ-5D VAS
    0.8 ( 18.56 )
    1.5 ( 20.33 )
    No statistical analyses for this end point

    Secondary: Time to Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

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    End point title
    		 Time to Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    End point description
    The time from the date of randomization to the first date observing ECOG PS ≥2 (that is, deterioration from baseline status of 0 or 1). Participants without PS deterioration were censored at their last documented assessments of 0 or 1. ECOG Performance Status: 2- Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours, 3 -Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours, 4 -Completely disabled. Cannot carry on any selfcare.Totally confined to bed or chair,5- Dead. APD: All randomized participants. Participants censored: Ramucirumab + Cisplatin + Capecitabine=254 and Placebo + Cisplatin + Capecitabine= 260.
    End point type
    Secondary
    End point timeframe
    Randomization to ECOG PS ≥2 (Up To 26 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    326 [1]
    319 [2]
    Units: months
        median (confidence interval 95%)
    999 (12.2 to 999)
    999 (999 to 999)
    Notes
    [1] - 999=NA. Very few events occurred therefore data were not assessable.
    [2] - 999=NA Very few events occurred therefore data were not assessable.
    Statistical analysis title
    		 Time to Deterioration ECOG and PS
    Comparison groups
    Ramucirumab + Cisplatin + Capecitabine v Placebo + Cisplatin + Capecitabine
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.58

    Secondary: Number of Participants with Anti-Ramucirumab Antibodies

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    End point title
    		 Number of Participants with Anti-Ramucirumab Antibodies
    End point description
    Participants who developed treatment-emergent antibody responses to Ramucirumab postbaseline. Analysis Population Description: All participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Predose Cycle 1 through 30 Days After Treatment Discontinuation (Up To 24 Months)
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine Placebo + Cisplatin + Capecitabine
    Number of subjects analysed
    323
    315
    Units: participants
    4
    5
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Ramucirumab

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    End point title
    		 Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Ramucirumab [3]
    End point description
    Pharmacokinetics (PK): Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Ramucirumab APD: All randomized participants who received ramucirumab and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 1 hour (hr) end of infusion (EOI), Cycle 3 Day 1: 1hr EOI, Cycle 9 Day 1: 1 hr EOI
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analysis were only planned for experimental arm Ramucirumab + Cisplatin + Capecitabine.
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine
    Number of subjects analysed
    283
    Units: Microgram/milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1
    133 ( 31 )
        Cycle 3, Day 1
    173 ( 35 )
        Cycle 9, Day 1
    169 ( 60 )
    No statistical analyses for this end point

    Secondary: PK: Minimum Concentration (Cmin) of Ramucirumab

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    End point title
    		 PK: Minimum Concentration (Cmin) of Ramucirumab [4]
    End point description
    Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab APD: All randomized participants who received ramucirumab and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 1 hour (hr) end of infusion (EOI), Cycle 3 Day 1: 1hr EOI, Cycle 9 Day 1: 1 hr EOI
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analysis were only planned for experimental arm Ramucirumab + Cisplatin + Capecitabine.
    End point values
    		 Ramucirumab + Cisplatin + Capecitabine
    Number of subjects analysed
    268
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 8
    40.7 ( 35 )
        Cycle 2, Day 1
    35.7 ( 56 )
        Cycle 3, Day 1
    51.2 ( 47 )
        Cycle 5, Day 1
    69.7 ( 52 )
        Cycle 9, Day 1
    77.6 ( 98 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline Up to 5.6 Years
    Adverse event reporting additional description
    All participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo+Capecitabine+Cisplatin
    Reporting group description
    		 Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.

    Reporting group title
    LY3009806+Capecitabine+Cisplatin
    Reporting group description
    		 8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.

    Serious adverse events
    		 Placebo+Capecitabine+Cisplatin LY3009806+Capecitabine+Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    150 / 315 (47.62%)
    161 / 323 (49.85%)
         number of deaths (all causes)
    21
    19
         number of deaths resulting from adverse events
    8
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    colorectal cancer
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malignant pleural effusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    metastases to peritoneum
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tumour associated fever
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tumour haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    arterial thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    brachiocephalic vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    circulatory collapse
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    deep vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    embolism arterial
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    embolism venous
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (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 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypovolaemic shock
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    orthostatic hypotension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    phlebitis deep
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subclavian vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombophlebitis superficial
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis limb
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    complication associated with device
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    death
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    device occlusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    5 / 315 (1.59%)
    6 / 323 (1.86%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    heparin-induced thrombocytopenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    impaired healing
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infusion related reaction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mucosal inflammation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multiple organ dysfunction syndrome
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    12 / 315 (3.81%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    3 / 12
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hiccups
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoxia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung disorder
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia aspiration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    pneumothorax spontaneous
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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 23.0
         subjects affected / exposed
    9 / 315 (2.86%)
    7 / 323 (2.17%)
         occurrences causally related to treatment / all
    7 / 9
    5 / 7
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    respiratory failure
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    delirium
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood bilirubin increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood creatinine increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood potassium decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    body temperature increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    creatinine renal clearance decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutrophil count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    platelet count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    weight decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    white blood cell count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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
    accidental overdose
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device dislocation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal stoma complication
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin laceration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vascular access complication
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    angina pectoris
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    arrhythmia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    arrhythmia supraventricular
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrioventricular block complete
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac arrest
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    cardiac disorder
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cardiogenic shock
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    pericardial effusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sinus bradycardia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sinus node dysfunction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    supraventricular extrasystoles
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tachycardia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral infarction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebrovascular accident
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    cognitive disorder
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhage intracranial
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nervous system disorder
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    presyncope
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    11 / 315 (3.49%)
    11 / 323 (3.41%)
         occurrences causally related to treatment / all
    13 / 16
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood loss anaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bone marrow failure
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    11 / 315 (3.49%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    12 / 13
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemolytic anaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    8 / 315 (2.54%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    9 / 9
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancytopenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    retinal vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (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 distension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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 23.0
         subjects affected / exposed
    7 / 315 (2.22%)
    13 / 323 (4.02%)
         occurrences causally related to treatment / all
    0 / 10
    3 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain upper
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal rigidity
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    acute abdomen
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    constipation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    19 / 315 (6.03%)
    11 / 323 (3.41%)
         occurrences causally related to treatment / all
    16 / 20
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    7 / 315 (2.22%)
    8 / 323 (2.48%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enteritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enterocolitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enterocutaneous fistula
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    erosive oesophagitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    gastric perforation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    9 / 323 (2.79%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric ulcer haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastric ulcer perforation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal obstruction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematemesis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematochezia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hiatus hernia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    ileus paralytic
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    impaired gastric emptying
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    intestinal perforation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intra-abdominal haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    large intestinal stenosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    melaena
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    8 / 315 (2.54%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    9 / 10
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    obstruction gastric
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal fistula
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophageal stenosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumoperitoneum
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestinal perforation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    subileus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    22 / 315 (6.98%)
    14 / 323 (4.33%)
         occurrences causally related to treatment / all
    20 / 27
    9 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct obstruction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic failure
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    hyperbilirubinaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    dermatomyositis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin disorder
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    8 / 315 (2.54%)
    10 / 323 (3.10%)
         occurrences causally related to treatment / all
    10 / 13
    8 / 10
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    hydronephrosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nephritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nephropathy
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    proteinuria
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyelocaliectasis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal colic
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal impairment
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteonecrosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    biliary tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         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 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cystitis bacterial
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related sepsis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enterocolitis infectious
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (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 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    periodontitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    periorbital infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    pharyngitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    7 / 315 (2.22%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    pneumonia bacterial
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudomembranous colitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudomonas infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyelonephritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    5 / 315 (1.59%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    septic shock
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    vascular device infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    cachexia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    decreased appetite
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    3 / 315 (0.95%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    1 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    9 / 315 (2.86%)
    7 / 323 (2.17%)
         occurrences causally related to treatment / all
    4 / 9
    4 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperkalaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    4 / 315 (1.27%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypomagnesaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    2 / 315 (0.63%)
    6 / 323 (1.86%)
         occurrences causally related to treatment / all
    2 / 2
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypophosphataemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malnutrition
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    1 / 315 (0.32%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    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+Capecitabine+Cisplatin LY3009806+Capecitabine+Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    304 / 315 (96.51%)
    315 / 323 (97.52%)
    Vascular disorders
    embolism venous
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    17 / 315 (5.40%)
    13 / 323 (4.02%)
         occurrences all number
    17
    13
    hypertension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    23 / 315 (7.30%)
    70 / 323 (21.67%)
         occurrences all number
    30
    152
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    40 / 315 (12.70%)
    44 / 323 (13.62%)
         occurrences all number
    101
    133
    fatigue
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    145 / 315 (46.03%)
    153 / 323 (47.37%)
         occurrences all number
    309
    316
    mucosal inflammation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    17 / 315 (5.40%)
    20 / 323 (6.19%)
         occurrences all number
    41
    31
    oedema peripheral
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    33 / 315 (10.48%)
    45 / 323 (13.93%)
         occurrences all number
    46
    65
    pyrexia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    40 / 315 (12.70%)
    28 / 323 (8.67%)
         occurrences all number
    56
    37
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    18 / 315 (5.71%)
    25 / 323 (7.74%)
         occurrences all number
    18
    29
    dyspnoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    21 / 315 (6.67%)
    36 / 323 (11.15%)
         occurrences all number
    26
    49
    epistaxis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    14 / 315 (4.44%)
    48 / 323 (14.86%)
         occurrences all number
    19
    76
    hiccups
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    33 / 315 (10.48%)
    36 / 323 (11.15%)
         occurrences all number
    46
    63
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    25 / 315 (7.94%)
    27 / 323 (8.36%)
         occurrences all number
    27
    29
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    10 / 315 (3.17%)
    19 / 323 (5.88%)
         occurrences all number
    15
    29
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    12 / 315 (3.81%)
    20 / 323 (6.19%)
         occurrences all number
    17
    25
    blood creatinine increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    28 / 315 (8.89%)
    31 / 323 (9.60%)
         occurrences all number
    41
    60
    neutrophil count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    92 / 315 (29.21%)
    103 / 323 (31.89%)
         occurrences all number
    263
    295
    platelet count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    33 / 315 (10.48%)
    72 / 323 (22.29%)
         occurrences all number
    75
    254
    weight decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    37 / 315 (11.75%)
    54 / 323 (16.72%)
         occurrences all number
    56
    72
    white blood cell count decreased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    32 / 315 (10.16%)
    37 / 323 (11.46%)
         occurrences all number
    109
    118
    Nervous system disorders
    dysgeusia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    27 / 315 (8.57%)
    34 / 323 (10.53%)
         occurrences all number
    31
    38
    dizziness
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    35 / 315 (11.11%)
    36 / 323 (11.15%)
         occurrences all number
    52
    42
    headache
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    27 / 315 (8.57%)
    43 / 323 (13.31%)
         occurrences all number
    36
    57
    neuropathy peripheral
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    8 / 315 (2.54%)
    20 / 323 (6.19%)
         occurrences all number
    9
    30
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    31 / 315 (9.84%)
    39 / 323 (12.07%)
         occurrences all number
    41
    62
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    114 / 315 (36.19%)
    104 / 323 (32.20%)
         occurrences all number
    289
    276
    neutropenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    74 / 315 (23.49%)
    71 / 323 (21.98%)
         occurrences all number
    133
    218
    thrombocytopenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    26 / 315 (8.25%)
    41 / 323 (12.69%)
         occurrences all number
    51
    106
    Ear and labyrinth disorders
    tinnitus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    27 / 315 (8.57%)
    23 / 323 (7.12%)
         occurrences all number
    32
    26
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    51 / 315 (16.19%)
    52 / 323 (16.10%)
         occurrences all number
    69
    80
    abdominal pain upper
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    15 / 315 (4.76%)
    22 / 323 (6.81%)
         occurrences all number
    22
    27
    constipation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    78 / 315 (24.76%)
    104 / 323 (32.20%)
         occurrences all number
    107
    161
    diarrhoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    107 / 315 (33.97%)
    108 / 323 (33.44%)
         occurrences all number
    175
    175
    dyspepsia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    12 / 315 (3.81%)
    19 / 323 (5.88%)
         occurrences all number
    14
    20
    dysphagia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    17 / 315 (5.40%)
    21 / 323 (6.50%)
         occurrences all number
    23
    33
    nausea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    186 / 315 (59.05%)
    205 / 323 (63.47%)
         occurrences all number
    444
    459
    stomatitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    39 / 315 (12.38%)
    67 / 323 (20.74%)
         occurrences all number
    64
    110
    vomiting
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    117 / 315 (37.14%)
    134 / 323 (41.49%)
         occurrences all number
    217
    249
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    16 / 315 (5.08%)
    19 / 323 (5.88%)
         occurrences all number
    20
    21
    dry skin
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    16 / 315 (5.08%)
    20 / 323 (6.19%)
         occurrences all number
    17
    23
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    63 / 315 (20.00%)
    99 / 323 (30.65%)
         occurrences all number
    121
    248
    skin hyperpigmentation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    10 / 315 (3.17%)
    18 / 323 (5.57%)
         occurrences all number
    10
    18
    Renal and urinary disorders
    proteinuria
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    36 / 315 (11.43%)
    64 / 323 (19.81%)
         occurrences all number
    60
    156
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    16 / 315 (5.08%)
    28 / 323 (8.67%)
         occurrences all number
    20
    33
    Infections and infestations
    upper respiratory tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    17 / 315 (5.40%)
    8 / 323 (2.48%)
         occurrences all number
    18
    11
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    100 / 315 (31.75%)
    130 / 323 (40.25%)
         occurrences all number
    190
    245
    dehydration
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    25 / 315 (7.94%)
    19 / 323 (5.88%)
         occurrences all number
    30
    25
    hypoalbuminaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    13 / 315 (4.13%)
    17 / 323 (5.26%)
         occurrences all number
    21
    28
    hypocalcaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    11 / 315 (3.49%)
    20 / 323 (6.19%)
         occurrences all number
    21
    23
    hypokalaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    40 / 315 (12.70%)
    36 / 323 (11.15%)
         occurrences all number
    68
    51
    hypomagnesaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    45 / 315 (14.29%)
    36 / 323 (11.15%)
         occurrences all number
    97
    47
    hyponatraemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    17 / 315 (5.40%)
    18 / 323 (5.57%)
         occurrences all number
    21
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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