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    Clinical Trial Results:
    A Multicenter, Single arm, Open Label Clinical Trial to Evaluate the Safety and Health-Related Quality of Life of Aflibercept in Patients with Metastatic Colorectal Cancer (mCRC) Previously Treated with an Oxaliplatin-Containing Regimen

    Summary
    EudraCT number
    2011-005724-17
    Trial protocol
    BE   SE   DK   FI   DE   NL   IT   ES   IE   CZ   SI   HU  
    Global end of trial date
    31 Jan 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    22 Apr 2018
    First version publication date
    15 Feb 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Update to baseline characteristics and endpoint description

    Trial information

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    Trial identification
    Sponsor protocol code
    AFLIBC06097
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01571284
    WHO universal trial number (UTN)
    U1111-1125-8949
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette , Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com
    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 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To provide mCRC subjects (similar to the subjects evaluated in the VELOUR [EFC10262] phase III trial) and investigators with access to aflibercept, prior to its marketing authorization and/or commercial availability and to document the aflibercept overall safety in this subject population.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 41
    Country: Number of subjects enrolled
    Canada: 49
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Lebanon: 7
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Thailand: 111
    Country: Number of subjects enrolled
    Turkey: 40
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Spain: 77
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    Czech Republic: 20
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 42
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Italy: 200
    Worldwide total number of subjects
    779
    EEA total number of subjects
    471
    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)
    475
    From 65 to 84 years
    303
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 151 sites in 23 countries. A total of 798 subjects were screened between 30 May 2012 and 03 January 2015, out of which 781 subjects were enrolled and 779 subjects were treated.

    Pre-assignment
    Screening details
    Subjects enrolled in the study to assess the safety of Aflibercept in subjects treated with a combination of Aflibercept with FOLFIRI regimen (Irinotecan, Leucovorin and 5-Fluorouracil [5-FU]). 403 subjects with disease progression (DP) and 209 with adverse events were considered as completed.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Arm description
    Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator’s decision or subject’s refusal of further treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Aflibercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Aflibercept (referred to also as VEGF-Trap or AVE0005) was to be provided as a 25 mg/mL concentrate solution for infusion.

    Number of subjects in period 1
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Started
    779
    Safety population
    779
    Completed
    612
    Not completed
    167
         Other than specified above
    80
         Subject's decision
    84
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Reporting group description
    Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator’s decision or subject’s refusal of further treatment.

    Reporting group values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin) Total
    Number of subjects
    779 779
    Age categorical
    Units: Subjects
    Age continuous
    Here Number analyzed = subjects analyzed for specified categories
    Units: years
        arithmetic mean (standard deviation)
    60.3 ± 11.0 -
    Gender categorical
    Units: Subjects
        Female
    314 314
        Male
    465 465
    Race/Ethnicity, Customized
    Units: Subjects
        White
    631 631
        Black or African
    8 8
        American Asian
    121 121
        Other
    19 19
    Location of Primary Tumor
    Units: Subjects
        Colon
    406 406
        Recto sigmoid
    171 171
        Rectum
    200 200
        Other
    2 2
    Histology
    Units: Subjects
        Adenocarcinoma
    778 778
        Other
    1 1
    Any Relevant Medical/Surgical History
    Any relevant medical/surgical history including detailed cardiovascular risk factors and prior vascular events if any.
    Units: Subjects
        Any Relevant Medical/Surgical History
    640 640
        Unknown
    139 139
    History of Thrombovascular Event and/or Presence of Cardiovascular Risk Factor
    Units: Subjects
        Thrombovascular Event and/or Presence of CV Risk
    424 424
        Unknown
    355 355
    Location of Primary Tumor
    Units: Subjects
        Colon
    406 406
        Recto sigmoid
    171 171
        Rectum
    200 200
        Other
    2 2
    Histology
    Units: Subjects
        Adenocarcinoma
    778 778
        Other
    1 1
    Organs with Metastases at Baseline
    Units: Subjects
        = 1
    358 358
        >1
    421 421
    Eastern Cooperative Oncology Group Performance Status (ECOG PS)
    Measure Description: ECOG PS is used to assess how the disease affects the daily living abilities of the subject. It ranges on the scale from 0-5 (0= normal activity; 1= symptoms but ambulatory; 2= in bed for less than (<) 50 percent (%) of the time; 3= in bed for greater than (>) 50% of the time; 4= 100% bedridden; 5= dead.
    Units: Subjects
        ECOG PS = 0
    484 484
        ECOG PS = 1
    292 292
        Missing
    3 3
    Body Surface Area (BSA)
    Units: m^2
        arithmetic mean (standard deviation)
    1.80 ± 0.23 -
    Systolic Blood Pressure
    Data for Systolic Blood Pressure is reported for a total of 776 subjects.
    Units: mmHg
        arithmetic mean (standard deviation)
    126.4 ± 13.4 -
    Diastolic Blood Pressure
    Data for Diastolic Blood Pressure is reported for a total of 776 subjects.
    Units: mmHg
        arithmetic mean (standard deviation)
    76.4 ± 9.0 -
    Time From Initial Histological Diagnosis till Baseline Visit
    Units: Months
        arithmetic mean (standard deviation)
    19.1 ± 17.2 -

    End points

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    End points reporting groups
    Reporting group title
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Reporting group description
    Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator’s decision or subject’s refusal of further treatment.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment.A serious adverse event: Any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening,required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included subjects with both serious and non-serious AEs. National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Version 4.03 was used to assess severity (Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling) of AEs. Safety population defined as the subjects who signed the informed consent form and received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: Subjects
        Any TEAE (All Grades)
    769
        Any TEAEs (Grades 3-4)
    609
        Any serious TEAE
    272
        Any serious related TEAE
    159
        Any TEAE leading to death
    47
        Any TEAE (permanent treatment discontinuation)
    208
        Any TEAE (premature treatment discontinuation)
    104
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Hematological Parameters During Treatment

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    End point title
    Number of Subjects With Abnormal Hematological Parameters During Treatment [2]
    End point description
    Abnormal hematological parameters included: anaemia, thrombocytopenia, leukopenia and neutropenia. Number of subjects with each of these parameters were analyzed by grades (All Grades and Grades 3-4 as per NCI CTCAE (Version 4.03), where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4. Safety population. Here, ‘n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: Subjects
        Anaemia: All Grades (n= 744)
    535
        Anaemia: Grades 3-4 (n= 744)
    14
        Thrombocytopenia: All Grades (n= 745)
    293
        Thrombocytopenia: Grades 3-4 (n= 745)
    13
        Leukopenia: All Grades (n =745)
    532
        Leukopenia: Grades 3-4 (n =745)
    72
        Neutropenia: All Grades (n= 744)
    450
        Neutropenia: Grades 3-4 (n= 744)
    227
    No statistical analyses for this end point

    Primary: Number of Subjects With International Normalized Ratio (INR)

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    End point title
    Number of Subjects With International Normalized Ratio (INR) [3]
    End point description
    The INR is a derived measure of the prothrombin time. The INR is the ratio of a subject’s prothrombin time to a normal control sample. Normal range (without anti coagulation therapy): 0.8-1.2; Targeted range (with anti coagulation therapy) 2.0-3.0. Safety population. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        INR<1.5 (n= 110)
    106
        INR>=1.5 to <3 (n =110)
    0
        INR>=3 to <5 (n =110)
    2
        INR>=5 (n =110)
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Electrolytes Parameters

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    End point title
    Number of Subjects With Abnormal Electrolytes Parameters [4]
    End point description
    Abnormal electrolytes parameters included: hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypokalemia, and hyperkalemia. Number of subjects with each of these parameters were analyzed by grades ( All Grades and Grades 3-4 as per NCI CTCAE Version 4.03, where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4. Safety population. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        Hyponatremia: All Grades (n= 736)
    181
        Hyponatremia: Grades 3-4 (n= 736)
    32
        Hypernatremia: All Grades (n= 736)
    75
        Hypernatremia: Grades 3-4 (n=736)
    1
        Hypocalcemia: All Grades (682)
    213
        Hypocalcemia: Grades 3-4 (682)
    5
        Hypercalcemia: All Grades (682)
    52
        Hypercalcemia: Grades 3-4 (682)
    2
        Hypokalemia: All Grades (734)
    121
        Hypokalemia: Grades 3-4 (734)
    16
        Hyperkalemia: All Grades (734)
    166
        Hyperkalemia: Grades 3-4 (734)
    10
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Renal and Liver Function Parameters

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    End point title
    Number of Subjects With Abnormal Renal and Liver Function Parameters [5]
    End point description
    Renal and liver function parameters included: creatinine, hyperbilirubinemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Number of subjects with each of these parameters were analyzed by grades (All Grades and Grades 3-4) as per NCI CTCAE version 4.03, where Grade 1=mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4. Safety population. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        Creatinine: All Grades (n= 737)
    161
        Creatinine: Grades 3-4 (n= 737)
    2
        Hyperbilirubinemia: All Grades (n= 734)
    130
        Hyperbilirubinemia: Grades 3-4 (n= 734)
    9
        AST: All Grades (n= 727)
    342
        AST: Grades 3-4 (n= 727)
    12
        ALT: All Grades (n= 736)
    270
        ALT: Grades 3-4 (n= 736)
    10
        Alkaline phosphatase: All Grades (n= 733)
    465
        Alkaline phosphatase: Grades 3-4 (n= 733)
    23
    No statistical analyses for this end point

    Primary: Creatinine Clearance of Aflibercept Plus FOLFIRI

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    End point title
    Creatinine Clearance of Aflibercept Plus FOLFIRI [6]
    End point description
    Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance was calculated using the Cockroft-Gault or Modification of Diet in Renal Disease (MDRD). Safety population. Here, subjects analysed = subjects evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    312
    Units: mL/min
        arithmetic mean (standard deviation)
    71.4 ± 29.3
    No statistical analyses for this end point

    Primary: Number of Subjects With Other Abnormal Biochemistry Parameters

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    End point title
    Number of Subjects With Other Abnormal Biochemistry Parameters [7]
    End point description
    Other abnormal biochemistry parameters included: hypoglycemia, hyperglycemia and hypoalbuminemia. Number of subjects with each of these parameters were analyzed by grades (All Grades and Grades 3-4) as per NCI CTCAE Version 4.03, where Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. All Grades included Grades 1-4. Safety population. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        Hypoglycemia: All Grades (n= 725)
    90
        Hypoglycemia: Grades 3-4 (n= 725)
    6
        Hyperglycemia: All Grades (n= 725)
    403
        Hyperglycemia: Grades 3-4 (n= 725)
    30
        Hypoalbuminemia: All Grades (n= 689)
    241
        Hypoalbuminemia: Grades 3-4 (n= 689)
    6
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Non-Gradable Biochemistry Parameters

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    End point title
    Number of Subjects With Abnormal Non-Gradable Biochemistry Parameters [8]
    End point description
    Non-gradeable biochemistry parameters included; chloride, urea, total protein, blood urea nitrogen (BUN) and lactate dehydrogenase (LDH). Number of subjects with <lower limit of normal ranges (LLN) and >upper limit of normal ranges (ULN) for each of these parameters were reported. Safety population. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        Chloride<LLN (n= 711)
    135
        Chloride>ULN (n= 711)
    217
        BUN<LLN (n= 258)
    41
        BUN>ULN (n= 258)
    83
        UREA<LLN (n= 591)
    60
        UREA>ULN (n= 591)
    250
        LDH<LLN (n= 723)
    79
        LDH>ULN (n= 723)
    423
        Total proteins<LLN (n= 711)
    162
        Total proteins>ULN (n= 711)
    77
    No statistical analyses for this end point

    Primary: Number of Subjects With Proteinuria Events

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    End point title
    Number of Subjects With Proteinuria Events [9]
    End point description
    Proteinuria is defined as the ratio of protein to creatinine. Number of subjects with proteinuria were analyzed by grades (Grades 1, 2, 3 ,4) as per NCI CTCAE Version 4.03 where Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening/disabling. Safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        Grade 1
    286
        Grade 2
    123
        Grade 3
    54
        Grade 4
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Proteinuria Grade >=2

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    End point title
    Number of Subjects With Proteinuria Grade >=2 [10]
    End point description
    Proteinuria is defined as the ratio of protein to creatinine. Number of subjects with proteinuria grade >=2 (graded as per NCI CTCAE Version 4.03), where Grade>=2 represents moderate to life-threatening/disabling event. Safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
    182
    No statistical analyses for this end point

    Primary: Number of Subjects With Urinary Protein-Creatinine Ratio (UPCR)

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    End point title
    Number of Subjects With Urinary Protein-Creatinine Ratio (UPCR) [11]
    End point description
    Urinary protein creatinine ratio (UPCR) corresponds to the ratio of the urinary protein and urinary creatinine concentration (expressed in mg/dL). This ratio provides an accurate quantification of 24-hours urinary protein excretion. There is a high correlation between morning UPCR and 24-hour proteinuria in subjects with normal or reduced renal functions. Normal ratio is < or = 1. Safety population. Here 'n' signifies number of subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        UPCR<=1 (n= 367)
    265
        UPCR>=1 to <=2 (n= 367)
    51
        UPCR>=2 to <=3 (n= 367)
    24
        UPCR>3 (n= 367)
    27
    No statistical analyses for this end point

    Primary: Number of Subjects With Proteinuria (Grade>=2) Concomitant With Hematuria and /or Hypertension

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    End point title
    Number of Subjects With Proteinuria (Grade>=2) Concomitant With Hematuria and /or Hypertension [12]
    End point description
    Proteinuria is defined as the presence of excess proteins in the urine (assessed either by spot sample, dipstick/ urine protein or 24 hour urine collection). Hematuria is defined as the presence of blood in urine (positive dipstick for RBC or reported AE). Number of subjects with proteinuria grade >=2 (graded as per NCI CTCAE Version 4.03), where Grade>=2 represents moderate to life-threatening/disabling event.Hypertension (high blood pressure) is defined as having a blood pressure reading of more than 140/90 mmHg over a number of weeks. Safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: subjects
        Proteinuria with hematuria
    72
        Proteinuria with hypertension
    4
        Proteinuria with hematuria and hypertension
    3
    No statistical analyses for this end point

    Primary: Number of Subjects With Cycle Delay and/or Dose Modification

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    End point title
    Number of Subjects With Cycle Delay and/or Dose Modification [13]
    End point description
    A theoretical cycle is a 2 week period i.e. 14 days. A cycle is delayed if duration of previous cycle is greater than 14+2 days ; dose modification includes dose reduction and dose omission. Safety population defined as the subjects who signed the informed consent form and received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Baseline up to 30 days after the last treatment administration (either Aflibercept or FOLFIRI whichever comes last) (maximum exposure: 214 weeks)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    779
    Units: Subjects
        No delay and no dose modification
    119
        Any delay and/or dose modification
    660
        Delay only
    163
        Delay and Aflibercept modified
    39
        Delay and FOLFIRI modified
    308
        Delay and Aflibercept and Folfiri modified
    97
        Only Aflibercept modified
    5
        Only FOLFIRI modified
    43
        Both Aflibercept and FOLFIRI modified
    5
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30 Score): Global Health Status

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    End point title
    Mean Change From Baseline in Health Related Quality of Life (HRQL) European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30 Score): Global Health Status
    End point description
    EORTC-QLQ-C30: cancer-specific instrument with 30 questions(Q). First 28 Q used 4-point scale(S)(1=not at all,2=a little,3=quite a bit,4=very much)for evaluating 5 functional S(physical,role,emotional,cognitive,social),3 symptom S (fatigue,nausea/vomiting,pain) & other single items. For each item,high score=high level symptomatology.Last 2Q=subject’s assessment of overall health & quality of life (qol) on 7-point S(1=very poor to 7=excellent).EORTC QLQ-C30 observed values & change from baseline(B) for global health status (scoring of Q 29 & 30) & 5 functional S,3 symptom S & other single items (scoring of Q1 to 28). Answers converted into grading S, with values between 0 & 100. High score=favourable outcome with best qol for subject. EORTC QLQ-C30 analysis population:subjects who signed informed consent form; had evaluable QLQ-C30 questionnaire at B & >=1 evaluable assessment post B & received at least part of 1 dose of study treatment.‘n’= subjects analysed at specified time-points.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at the end of treatment (EOT) (within 30 days of last treatment) (maximum exposure: 214 weeks)
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    636
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 630)
    68.61 ± 20.48
        Change at Cycle 3 (n= 549)
    -3.34 ± 18.83
        Change at Cycle 5 (n= 429)
    -4.70 ± 18.89
        Change at Cycle 7 (n= 344)
    -3.63 ± 22.02
        Change at Cycle 9 (n= 273)
    -3.97 ± 21.31
        Change at Cycle 11 (n= 232)
    -5.85 ± 22.26
        Change at Cycle 13 (n= 151)
    -2.26 ± 21.69
        Change at Cycle 15 (n= 123)
    -3.05 ± 22.46
        Change at Cycle 17 (n= 85)
    -1.18 ± 22.50
        Change at Cycle 19 (n= 60)
    -2.36 ± 22.92
        Change at Cycle 21 (n= 45)
    -5.56 ± 23.77
        Change at Cycle 23 (n= 34)
    -6.86 ± 19.94
        Change at Cycle 25 (n= 29)
    -8.05 ± 16.89
        Change at Cycle 27 (n= 23)
    -10.14 ± 17.58
        Change at Cycle 29 (n= 20)
    -8.33 ± 14.05
        Change at Cycle 31 (n= 15)
    -9.44 ± 16.92
        Change at Cycle 33 (n= 11)
    -11.36 ± 21.82
        Change at Cycle 35 (n =10)
    -5.83 ± 20.81
        Change at EOT (n= 340)
    -8.82 ± 23.95
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in HRQL EORTC QLQ-C30 Score: Functional Scales

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    End point title
    Mean Change From Baseline in HRQL EORTC QLQ-C30 Score: Functional Scales
    End point description
    EORTC-QLQ-C30: cancer-specific instrument with 30 questions (Q) for evaluation of new chemotherapy & provides an assessment of subject reported outcome dimensions. First 28 Q used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much)for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score=high level of symptomatology/problem. Last 2 Q=subject’s assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values & change from baseline for global health status (scoring of Q 29 & 30) & 5 functional scales, 3 symptom scales & other single items (scoring of Q 1 to 28).Answers were converted into grading scale, with values between 0 & 100. High score=favourable outcome with a best quality of life for subject. EORTC QLQ-C30 analysis population.'n' signifies =subjects analysed at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    636
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical - Baseline (n= 634)
    81.79 ± 19.41
        Physical - Change at Cycle 3 (n= 551)
    -3.73 ± 15.15
        Physical - Change at Cycle 5 (n= 439)
    -3.95 ± 15.22
        Physical - Change at Cycle 7 (n= 342)
    -4.62 ± 16.23
        Physical - Change at Cycle 9 (n= 275)
    -4.36 ± 15.79
        Physical - Change at Cycle 11 (n= 235)
    -6.99 ± 17.89
        Physical - Change at Cycle 13 (n= 154)
    -4.99 ± 16.17
        Physical - Change at Cycle 15 (n= 122)
    -3.54 ± 15.99
        Physical - Change at Cycle 17 (n= 87)
    -5.10 ± 16.20
        Physical - Change at Cycle 19 (n= 61)
    -5.68 ± 16.23
        Physical - Change at Cycle 21 (n= 46)
    -5.70 ± 13.01
        Physical - Change at Cycle 23 (n =36)
    -7.87 ± 14.38
        Physical - Change at Cycle 25 (n= 29)
    -5.75 ± 12.18
        Physical - Change at Cycle 27 (n= 23)
    -6.59 ± 11.64
        Physical - Change at Cycle 29 (n= 20)
    -7.67 ± 11.09
        Physical - Change at Cycle 31 (n= 15)
    -9.33 ± 14.65
        Physical - Change at Cycle 33 (n= 11)
    -5.45 ± 9.81
        Physical - Change at Cycle 35 (n= 10)
    -10.00 ± 13.05
        Physical - Change at EOT (n= 341)
    -11.16 ± 21.65
        Role - Baseline (n= 633)
    79.91 ± 26.25
        Role - Change at Cycle 3 (n= 551)
    -6.26 ± 25.22
        Role - Change at Cycle 5 (n= 442)
    -5.66 ± 23.26
        Role - Change at Cycle 7 (n= 342)
    -6.68 ± 24.29
        Role - Change at Cycle 9 (n= 275)
    -6.55 ± 23.95
        Role - Change at Cycle 11 (n= 234)
    -8.76 ± 26.35
        Role - Change at Cycle 13 (n= 154)
    -7.36 ± 23.41
        Role - Change at Cycle 15 (n= 123)
    -7.18 ± 21.98
        Role - Change at Cycle 17 (n= 87)
    -9.58 ± 22.54
        Role - Change at Cycle 19 (n= 61)
    -9.84 ± 22.44
        Role - Change at Cycle 21 (n= 46)
    -9.78 ± 18.11
        Role - Change at Cycle 23 (n= 36)
    -10.65 ± 18.32
        Role - Change at Cycle 25 (n= 29)
    -10.92 ± 17.97
        Role - Change at Cycle 27 (n= 23)
    -10.14 ± 17.22
        Role - Change at Cycle 29 (n= 20)
    -10.83 ± 17.33
        Role - Change at Cycle 31 (n= 15)
    -14.44 ± 18.76
        Role - Change at Cycle 33 (n= 11)
    -15.15 ± 15.73
        Role - Change at Cycle 35 (n= 10)
    -15.00 ± 16.57
        Role - Change at EOT (n= 340)
    -12.11 ± 28.22
        Emotional - Baseline (n= 634)
    78.96 ± 20.60
        Emotional - Change at Cycle 3 (n= 553)
    1.14 ± 19.95
        Emotional - Change at Cycle 5 (n =436)
    0.74 ± 19.32
        Emotional - Change at Cycle 7 (n= 344)
    1.58 ± 20.91
        Emotional - Change at Cycle 9 (n= 275)
    1.69 ± 21.38
        Emotional - Change at Cycle 11 (n= 235)
    0.08 ± 20.40
        Emotional - Change at Cycle 13 (n= 152)
    0.93 ± 20.08
        Emotional - Change at Cycle 15 (n= 124)
    2.51 ± 20.23
        Emotional - Change at Cycle 17 (n= 87)
    2.91 ± 18.23
        Emotional - Change at Cycle 19 (n= 60)
    1.39 ± 17.60
        Emotional - Change at Cycle 21 (n= 44)
    0.06 ± 17.86
        Emotional - Change at Cycle 23 (n= 35)
    1.75 ± 19.29
        Emotional - Change at Cycle 25 (n= 29)
    4.98 ± 15.86
        Emotional - Change at Cycle 27 (n= 23)
    1.57 ± 17.64
        Emotional - Change at Cycle 29 (n= 20)
    2.64 ± 17.88
        Emotional - Change at Cycle 31 (n= 15)
    1.30 ± 17.78
        Emotional - Change at Cycle 33 (n= 11)
    0.25 ± 3.82
        Emotional - Change at Cycle 35 (n= 10)
    -0.00 ± 5.56
        Emotional - Change at EOT (n= 345)
    -2.87 ± 22.52
        Cognitive - Baseline (n= 635)
    86.90 ± 19.26
        Cognitive - Change at Cycle 3 (n= 555)
    -1.77 ± 16.92
        Cognitive - Change at Cycle 5 (n= 437)
    -1.87 ± 16.58
        Cognitive - Change at Cycle 7 (n= 343)
    -1.99 ± 19.71
        Cognitive - Change at Cycle 9 (n= 275)
    -2.18 ± 20.17
        Cognitive - Change at Cycle 11 (n= 234)
    -4.27 ± 20.29
        Cognitive - Change at Cycle 13 (n= 153)
    -2.83 ± 17.40
        Cognitive - Change at Cycle 15 (n= 124)
    -2.28 ± 19.40
        Cognitive - Change at Cycle 17 (n= 87)
    -3.45 ± 19.38
        Cognitive - Change at Cycle 19 (n= 60)
    -5.00 ± 22.19
        Cognitive - Change at Cycle 21 (n= 45)
    -5.56 ± 16.28
        Cognitive - Change at Cycle 23 (n= 35)
    -5.71 ± 14.54
        Cognitive - Change at Cycle 25 (n= 29)
    -6.90 ± 21.14
        Cognitive - Change at Cycle 27 (n= 23)
    -5.80 ± 16.37
        Cognitive - Change at Cycle 29 (n= 20)
    -6.67 ± 18.26
        Cognitive - Change at Cycle 31 (n= 15)
    -5.56 ± 15.00
        Cognitive - Change at Cycle 33 (n= 11)
    -10.61 ± 17.12
        Cognitive - Change at Cycle 35 (n= 10)
    -11.67 ± 13.72
        Cognitive- Change at EOT (n= 345)
    -4.98 ± 22.67
        Social - Baseline (n= 634)
    80.57 ± 24.68
        Social - Change at Cycle 3 (n= 554)
    -2.05 ± 22.83
        Social - Change at Cycle 5 (n= 437)
    -2.86 ± 21.60
        Social - Change at Cycle 7 (n= 345)
    -4.78 ± 23.65
        Social - Change at Cycle 9 (n= 274)
    -4.56 ± 23.84
        Social - Change at Cycle 11 (n= 235)
    -7.09 ± 24.83
        Social - Change at Cycle 13 (n= 153)
    -5.56 ± 24.03
        Social - Change at Cycle 15 (n= 124)
    -6.18 ± 23.23
        Social - Change at Cycle 17 (n= 87)
    -5.56 ± 22.69
        Social - Change at Cycle 19 (n= 60)
    -5.28 ± 22.02
        Social - Change at Cycle 21 (n= 45)
    -5.56 ± 21.61
        Social - Change at Cycle 23 (n= 35)
    -7.62 ± 17.78
        Social - Change at Cycle 25 (n= 29)
    -4.60 ± 18.31
        Social - Change at Cycle 27 (n= 23)
    -2.17 ± 17.63
        Social - Change at Cycle 29 (n= 20)
    -5.00 ± 18.81
        Social - Change at Cycle 31 (n= 15)
    -7.78 ± 25.09
        Social - Change at Cycle 33 (n= 11)
    -1.52 ± 17.41
        Social - Change at Cycle 35 (n= 10)
    -1.67 ± 14.59
        Social - Change at EOT (n= 344)
    -9.01 ± 26.23
    No statistical analyses for this end point

    Secondary: Change From Baseline in HRQL EORTC QLQ-C30 Score: Symptom Scales

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    End point title
    Change From Baseline in HRQL EORTC QLQ-C30 Score: Symptom Scales
    End point description
    EORTC-QLQ-C30:cancer-specific instrument with 30 questions (Q) for evaluation of new chemotherapy & provides an assessment of subjects reported outcome dimensions. First 28 Q used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) & other single items. For each item,high score=high level of symptomatology/problem. Last 2 Q=subject’s assessment of overall health & quality of life, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values & change from baseline for global health status (scoring of Q 29 & 30) & 5 functional scales, 3 symptom scales & other single items (scoring of Q 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score=favorable outcome with a best quality of life for subject. EORTC QLQ-C30 analysis population. Here, ‘n’=subjects analysed at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    636
    Units: units on a scale
    arithmetic mean (standard deviation)
        Fatigue - Baseline (n= 633)
    29.16 ± 23.48
        Fatigue - Change at Cycle 3 (n =551)
    7.35 ± 21.62
        Fatigue - Change at Cycle 5 (n= 443)
    8.40 ± 21.88
        Fatigue - Change at Cycle 7 (n= 344)
    9.54 ± 22.60
        Fatigue - Change at Cycle 9 (n= 276)
    7.89 ± 21.80
        Fatigue - Change at Cycle 11 (n= 235)
    11.30 ± 23.73
        Fatigue - Change at Cycle 13 (n= 154)
    8.33 ± 21.72
        Fatigue - Change at Cycle 15 (n= 123)
    7.41 ± 22.38
        Fatigue - Change at Cycle 17 (n= 87)
    6.70 ± 21.25
        Fatigue - Change at Cycle 19 (n= 61)
    8.93 ± 19.83
        Fatigue - Change at Cycle 21 (n= 46)
    10.39 ± 17.90
        Fatigue - Change at Cycle 23 (n= 36)
    10.80 ± 18.49
        Fatigue - Change at Cycle 25 (n= 29)
    7.66 ± 19.94
        Fatigue - Change at Cycle 27 (n= 23)
    9.66 ± 18.74
        Fatigue - Change at Cycle 29 (n= 20)
    11.67 ± 18.55
        Fatigue - Change at Cycle 31 (n= 15)
    14.07 ± 21.61
        Fatigue - Change at Cycle 33 (n= 11)
    15.15 ± 21.81
        Fatigue - Change at Cycle 35 (n= 10)
    14.44 ± 18.92
        Fatigue - Change at EOT (n= 343)
    12.31 ± 25.56
        Nausea and Vomiting - Baseline (n= 635)
    5.88 ± 13.99
        Nausea and Vomiting - Change at Cycle 3 (n= 554)
    6.68 ± 19.81
        Nausea and Vomiting - Change at Cycle 5 (n= 442)
    6.98 ± 19.79
        Nausea and Vomiting - Change at Cycle 7 (n= 343)
    6.61 ± 18.07
        Nausea and Vomiting - Change at Cycle 9 (n= 277)
    6.20 ± 19.68
        Nausea and Vomiting - Change at Cycle 11 (n= 236)
    8.97 ± 19.83
        Nausea and Vomiting - Change at Cycle 13 (n= 154)
    6.82 ± 14.71
        Nausea and Vomiting - Change at Cycle 15 (n= 124)
    6.85 ± 16.33
        Nausea and Vomiting - Change at Cycle 17 (n= 87)
    3.45 ± 15.49
        Nausea and Vomiting - Change at Cycle 19 (n= 61)
    6.56 ± 14.04
        Nausea and Vomiting - Change at Cycle 21 (n= 46)
    3.99 ± 14.14
        Nausea and Vomiting - Change at Cycle 23 (n= 36)
    7.87 ± 10.90
        Nausea and Vomiting - Change at Cycle 25 (n= 29)
    4.02 ± 8.52
        Nausea and Vomiting - Change at Cycle 27 (n= 23)
    7.25 ± 11.04
        Nausea and Vomiting - Change at Cycle 29 (n= 20)
    1.67 ± 5.13
        Nausea and Vomiting - Change at Cycle 31 (n= 15)
    13.33 ± 28.31
        Nausea and Vomiting - Change at Cycle 33 (n= 11)
    3.03 ± 6.74
        Nausea and Vomiting - Change at Cycle 35 (n= 10)
    3.33 ± 7.03
        Nausea and Vomiting - Change at EOT (n= 344)
    6.64 ± 21.11
        Pain - Baseline (n= 636)
    20.47 ± 25.08
        Pain - Change at Cycle 3 (n= 554)
    2.68 ± 25.02
        Pain - Change at Cycle 5 (n= 444)
    2.52 ± 23.48
        Pain - Change at Cycle 7 (n= 345)
    3.00 ± 24.98
        Pain - Change at Cycle 9 (n= 276)
    2.72 ± 24.45
        Pain - Change at Cycle 11 (n= 236)
    6.64 ± 23.68
        Pain - Change at Cycle 13 (n= 155)
    5.16 ± 19.79
        Pain - Change at Cycle 15 (n= 124)
    7.26 ± 21.91
        Pain - Change at Cycle 17 (n= 87)
    9.39 ± 22.97
        Pain - Change at Cycle 19 (n= 61)
    8.74 ± 22.28
        Pain - Change at Cycle 21 (n= 46)
    7.25 ± 18.14
        Pain - Change at Cycle 23 (n= 36)
    8.33 ± 19.31
        Pain - Change at Cycle 25 (n= 29)
    5.75 ± 21.02
        Pain - Change at Cycle 27 (n= 23)
    5.07 ± 17.72
        Pain - Change at Cycle 29 (n= 20)
    4.17 ± 16.11
        Pain - Change at Cycle 31 (n= 15)
    10.00 ± 23.40
        Pain - Change at Cycle 33 (n= 11)
    7.58 ± 22.81
        Pain - Change at Cycle 35 (n= 10)
    6.67 ± 21.08
        Pain - Change at EOT (n= 347)
    10.85 ± 28.99
        Dyspnoea - Baseline (n= 627)
    13.45 ± 22.01
        Dyspnoea - Change at Cycle 3 (n= 542)
    3.63 ± 22.96
        Dyspnoea - Change at Cycle 5 (n= 435)
    5.75 ± 24.06
        Dyspnoea - Change at Cycle 7 (n= 339)
    6.98 ± 24.47
        Dyspnoea - Change at Cycle 9 (n= 271)
    6.89 ± 24.38
        Dyspnoea - Change at Cycle 11 (n= 232)
    8.19 ± 26.59
        Dyspnoea - Change at Cycle 13 (n= 152)
    6.36 ± 25.37
        Dyspnoea - Change at Cycle 15 (n= 121)
    3.58 ± 24.65
        Dyspnoea - Change at Cycle 17 (n= 84)
    5.16 ± 24.54
        Dyspnoea - Change at Cycle 19 (n= 59)
    6.78 ± 26.82
        Dyspnoea - Change at Cycle 21 (n= 44)
    3.79 ± 22.98
        Dyspnoea - Change at Cycle 23 (n= 33)
    4.04 ± 20.00
        Dyspnoea - Change at Cycle 25 (n= 27)
    1.23 ± 21.64
        Dyspnoea - Change at Cycle 27 (n= 22)
    3.03 ± 22.79
        Dyspnoea - Change at Cycle 29 (n= 19)
    -1.75 ± 23.50
        Dyspnoea - Change at Cycle 31 (n= 14)
    16.67 ± 28.50
        Dyspnoea - Change at Cycle 33 (n= 10)
    16.67 ± 17.57
        Dyspnoea - Change at Cycle 35 (n= 10)
    16.67 ± 23.57
        Dyspnoea - Change at EOT (n= 337)
    6.53 ± 25.79
        Insomnia - Baseline (n= 628)
    24.15 ± 28.09
        Insomnia - Change at Cycle 3 (n= 544)
    0.37 ± 27.36
        Insomnia - Change at Cycle 5 (n= 438)
    -0.08 ± 28.48
        Insomnia - Change at Cycle 7 (n= 338)
    -2.37 ± 29.63
        Insomnia - Change at Cycle 9 (n= 274)
    -0.24 ± 29.37
        Insomnia - Change at Cycle 11 (n= 234)
    2.56 ± 28.86
        Insomnia - Change at Cycle 13 (n= 153)
    0.65 ± 26.89
        Insomnia - Change at Cycle 15 (n= 122)
    -2.19 ± 27.01
        Insomnia - Change at Cycle 17 (n= 87)
    -1.92 ± 25.60
        Insomnia - Change at Cycle 19 (n= 61)
    1.64 ± 23.12
        Insomnia - Change at Cycle 21 (n= 45)
    0.74 ± 25.11
        Insomnia - Change at Cycle 23 (n= 36)
    -0.93 ± 33.32
        Insomnia - Change at Cycle 25 (n= 29)
    -0.00 ± 28.17
        Insomnia - Change at Cycle 27 (n= 22)
    -1.52 ± 24.07
        Insomnia - Change at Cycle 29 (n= 20)
    -3.33 ± 30.40
        Insomnia - Change at Cycle 31 (n= 15)
    -4.44 ± 41.53
        Insomnia - Change at Cycle 33 (n= 11)
    -6.06 ± 32.72
        Insomnia - Change at Cycle 35 (n= 10)
    -3.33 ± 33.15
        Insomnia - Change at EOT (n= 339)
    5.31 ± 32.50
        Appetite loss - Baseline (n= 631)
    17.38 ± 26.01
        Appetite loss - Change at Cycle 3 (n= 546)
    9.10 ± 28.64
        Appetite loss - Change at Cycle 5 (n= 436)
    9.02 ± 28.14
        Appetite loss - Change at Cycle 7 (n= 342)
    9.84 ± 27.80
        Appetite loss - Change at Cycle 9 (n= 274)
    9.98 ± 27.18
        Appetite loss - Change at Cycle 11 (n= 234)
    14.53 ± 28.27
        Appetite loss - Change at Cycle 13 (n= 150)
    10.67 ± 27.12
        Appetite loss - Change at Cycle 15 (n= 121)
    10.74 ± 25.90
        Appetite loss - Change at Cycle 17 (n= 86)
    8.91 ± 24.75
        Appetite loss - Change at Cycle 19 (n= 61)
    9.84 ± 24.60
        Appetite loss - Change at Cycle 21 (n= 46)
    13.04 ± 25.80
        Appetite loss - Change at Cycle 23 (n= 35)
    12.38 ± 25.67
        Appetite loss - Change at Cycle 25 (n= 29)
    11.49 ± 20.46
        Appetite loss - Change at Cycle 27 (n= 23)
    15.94 ± 22.18
        Appetite loss - Change at Cycle 29 (n= 20)
    15.00 ± 20.16
        Appetite loss - Change at Cycle 31 (n= 15)
    15.56 ± 24.77
        Appetite loss - Change at Cycle 33 (n= 11)
    15.15 ± 22.92
        Appetite loss - Change at Cycle 35 (n= 10)
    16.67 ± 17.57
        Appetite loss - Change at EOT (n= 338)
    12.03 ± 33.48
        Constipation - Baseline (n= 632)
    12.71 ± 21.61
        Constipation - Change at Cycle 3 (n= 550)
    2.42 ± 25.25
        Constipation - Change at Cycle 5 (n= 433)
    3.77 ± 26.52
        Constipation - Change at Cycle 7 (n= 342)
    2.63 ± 26.09
        Constipation - Change at Cycle 9 (n= 274)
    5.35 ± 26.68
        Constipation - Change at Cycle 11 (n= 234)
    4.42 ± 26.47
        Constipation - Change at Cycle 13 (n= 153)
    4.58 ± 25.95
        Constipation - Change at Cycle 15 (n= 122)
    4.92 ± 26.30
        Constipation - Change at Cycle 17 (n= 86)
    5.43 ± 23.35
        Constipation - Change at Cycle 19 (n= 60)
    8.33 ± 21.81
        Constipation - Change at Cycle 21 (n= 44)
    6.06 ± 18.00
        Constipation - Change at Cycle 23 (n= 36)
    9.26 ± 21.98
        Constipation - Change at Cycle 25 (n= 29)
    5.75 ± 17.97
        Constipation - Change at Cycle 27 (n= 23)
    1.45 ± 12.22
        Constipation - Change at Cycle 29 (n= 20)
    6.67 ± 20.52
        Constipation - Change at Cycle 31 (n= 15)
    22.22 ± 32.53
        Constipation - Change at Cycle 33 (n= 11)
    12.12 ± 16.82
        Constipation - Change at Cycle 35 (n= 10)
    10.00 ± 16.10
        Constipation - Change at EOT (n= 344)
    3.78 ± 27.33
        Diarrhoea - Baseline (n= 633)
    10.37 ± 19.47
        Diarrhoea - Change at Cycle 3 (n= 549)
    11.72 ± 28.16
        Diarrhoea - Change at Cycle 5 (n= 433)
    10.85 ± 28.29
        Diarrhoea - Change at Cycle 7 (n= 344)
    14.63 ± 29.94
        Diarrhoea - Change at Cycle 9 (n= 274)
    11.44 ± 26.44
        Diarrhoea - Change at Cycle 11 (n= 235)
    15.46 ± 27.26
        Diarrhoea - Change at Cycle 13 (n= 151)
    11.26 ± 24.00
        Diarrhoea - Change at Cycle 15 (n= 121)
    11.02 ± 28.02
        Diarrhoea - Change at Cycle 17 (n= 87)
    10.34 ± 21.75
        Diarrhoea - Change at Cycle 19 (n= 59)
    15.25 ± 25.76
        Diarrhoea - Change at Cycle 21 (n= 45)
    14.07 ± 24.09
        Diarrhoea - Change at Cycle 23 (n= 36)
    18.52 ± 21.74
        Diarrhoea - Change at Cycle 25 (n= 29)
    10.34 ± 22.01
        Diarrhoea - Change at Cycle 27 (n= 22)
    13.64 ± 19.68
        Diarrhoea - Change at Cycle 29 (n= 20)
    16.67 ± 25.36
        Diarrhoea - Change at Cycle 31 (n= 15)
    20.00 ± 24.56
        Diarrhoea - Change at Cycle 33 (n= 11)
    18.18 ± 22.92
        Diarrhoea - Change at Cycle 35 (n= 10)
    30.00 ± 18.92
        Diarrhoea - Change at EOT (n= 342)
    7.31 ± 24.26
        Financial difficulties - Baseline (n= 628)
    20.12 ± 30.25
        Financial difficulties - Change at Cycle 3 (n= 547
    -1.83 ± 23.80
        Financial difficulties - Change at Cycle 5 (n=430)
    -1.32 ± 24.00
        Financial difficulties - Change at Cycle 7 (n=337)
    -0.99 ± 27.68
        Financial difficulties - Change at Cycle 9 (n=270)
    -0.49 ± 26.80
        Financial difficulties - Change at Cycle 11(n=232)
    3.30 ± 25.64
        Financial difficulties - Change at Cycle 13(n=150)
    1.11 ± 27.96
        Financial difficulties - Change at Cycle 15(n=122)
    -0.27 ± 27.94
        Financial difficulties - Change at Cycle 17 (n=87)
    0.77 ± 27.36
        Financial difficulties - Change at Cycle 19 (n=60)
    1.67 ± 29.70
        Financial difficulties - Change at Cycle 21 (n=45)
    4.44 ± 25.23
        Financial difficulties - Change at Cycle 23 (n=34)
    2.94 ± 23.74
        Financial difficulties - Change at Cycle 25 (n=29)
    -4.60 ± 19.36
        Financial difficulties - Change at Cycle 27 (n=23)
    -2.90 ± 24.44
        Financial difficulties - Change at Cycle 29 (n=20)
    0.00 ± 21.63
        Financial difficulties - Change at Cycle 31 (n=15)
    -2.22 ± 19.79
        Financial difficulties - Change at Cycle 33 (n=11)
    -3.03 ± 17.98
        Financial difficulties - Change at Cycle 35 (n=10)
    0.00 ± 15.71
        Financial difficulties - Change at EOT (n=337)
    2.97 ± 27.90
    No statistical analyses for this end point

    Secondary: Change From Baseline in HRQL EQ-5D-3L Quality of Life: Single Index Utility Score

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    End point title
    Change From Baseline in HRQL EQ-5D-3L Quality of Life: Single Index Utility Score
    End point description
    EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and Visual Analogue Scale (VAS). EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state. EQ-5D analysis population: subjects who signed informed consent form, had an evaluable EQ-5D questionnaire at baseline and at least one evaluable assessment post baseline and received at least part of one dose of study treatment (either Aflibercept or FOLFIRI). Here, ‘n'=subjects analyzed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    623
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 623)
    0.77 ± 0.24
        Change at Cycle 3 (n= 536)
    -0.02 ± 0.23
        Change at Cycle 5 (n= 428)
    -0.03 ± 0.22
        Change at Cycle 7 (n= 335)
    -0.04 ± 0.23
        Change at Cycle 9 (n= 269)
    -0.05 ± 0.24
        Change at Cycle 11 (n= 226)
    -0.07 ± 0.25
        Change at Cycle 13 (n= 149)
    -0.05 ± 0.20
        Change at Cycle 15 (n= 119)
    -0.06 ± 0.23
        Change at Cycle 17 (n= 81)
    -0.05 ± 0.24
        Change at Cycle 19 (n= 58)
    -0.05 ± 0.18
        Change at Cycle 21 (n= 44)
    -0.09 ± 0.20
        Change at Cycle 23 (n= 34)
    -0.14 ± 0.26
        Change at Cycle 25 (n= 28)
    -0.08 ± 0.21
        Change at Cycle 27 (n= 23)
    -0.08 ± 0.21
        Change at Cycle 29 (n= 20)
    -0.08 ± 0.20
        Change at Cycle 31 (n= 15)
    -0.12 ± 0.30
        Change at Cycle 33 (n= 11)
    0.02 ± 0.14
        Change at Cycle 35 (n= 10)
    -0.05 ± 0.14
        Change at EOT (n= 343)
    -0.11 ± 0.30
    No statistical analyses for this end point

    Secondary: Change From Baseline in HRQL EQ-5D-3L VAS Score

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    End point title
    Change From Baseline in HRQL EQ-5D-3L VAS Score
    End point description
    EQ-5D was a standardized HRQL questionnaire consisting of EQ-5D descriptive system and VAS. EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels (no problem, some problems & severe problems) within a particular EQ-5D dimension. 5 dimensional 3-level system was converted into single index utility score. The VAS recorded the respondent’s self-rated health on a vertical visual analogue scale. The VAS ‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst imaginable health state) at the bottom. This information can be used as a quantitative measure of health outcome as judged by the individual respondents. EQ-5D analysis population. Here, ‘n’=subjects analysed at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline, Day 1 of every odd cycle (from Cycle 3 to 35); at EOT (within 30 days of last treatment) (maximum exposure: 214 weeks)
    End point values
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Number of subjects analysed
    623
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 577)
    72.81 ± 18.28
        Change at Cycle 3 (n= 482)
    -1.85 ± 15.35
        Change at Cycle 5 (n= 381)
    -2.15 ± 14.31
        Change at Cycle 7 (n= 303)
    -2.20 ± 16.33
        Change at Cycle 9 (n= 236)
    -2.74 ± 14.28
        Change at Cycle 11 (n= 203)
    -3.10 ± 14.40
        Change at Cycle 13 (n= 134)
    -2.36 ± 15.29
        Change at Cycle 15 (n= 103)
    -1.05 ± 15.51
        Change at Cycle 17 (n= 74)
    -1.91 ± 13.54
        Change at Cycle 19 (n= 52)
    -3.06 ± 13.85
        Change at Cycle 21 (n= 38)
    -2.13 ± 14.98
        Change at Cycle 23 (n= 30)
    -5.77 ± 13.50
        Change at Cycle 25 (n= 25)
    -7.28 ± 10.53
        Change at Cycle 27 (n= 17)
    -4.94 ± 8.68
        Change at Cycle 29 (n= 15)
    -8.80 ± 10.12
        Change at Cycle 31 (n= 13)
    -6.69 ± 12.61
        Change at Cycle 33 (n= 10)
    -7.90 ± 13.08
        Change at Cycle 35 (n= 8)
    -8.88 ± 11.53
        Change at EOT (n= 310)
    -6.67 ± 17.38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from signature of the informed consent form up to the final visit (214 weeks) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during ‘on-treatment period’ (from the first dose of treatment to 30 days after the last dose of treatment [either aflibercept or FOLFIRI]). Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Reporting group description
    Aflibercept 4 mg/kg IV infusion over 60 minutes followed by Irinotecan 180 mg/m^2 IV infusion over 90 minutes and Leucovorin 400 mg/m^2 IV infusion over 120 minutes at the same time followed by 5-FU 400 mg/m^2 IV bolus over 2-4 minutes followed by 5-FU 2400 mg/m^2 continuous IV infusion over 46 hours on Day 1 of each cycle (1 Cycle = 2 weeks), until DP, unacceptable toxicity, death, Investigator’s decision or subject’s refusal of further treatment.

    Serious adverse events
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    272 / 779 (34.92%)
         number of deaths (all causes)
    48
         number of deaths resulting from adverse events
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    11 / 779 (1.41%)
         occurrences causally related to treatment / all
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vena Cava Thrombosis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Cancer Surgery
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases To Central Nervous System
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cancer Pain
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour Associated Fever
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic Shock
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Disease Progression
         subjects affected / exposed
    23 / 779 (2.95%)
         occurrences causally related to treatment / all
    0 / 23
         deaths causally related to treatment / all
    0 / 19
    General Physical Health Deterioration
         subjects affected / exposed
    5 / 779 (0.64%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    2 / 2
    Malaise
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pain
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    12 / 779 (1.54%)
         occurrences causally related to treatment / all
    6 / 18
         deaths causally related to treatment / all
    0 / 0
    Sudden Death
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Injury, poisoning and procedural complications
    Accidental Exposure To Product
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Accidental Overdose
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anastomotic Leak
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Contrast Media Reaction
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Stoma Complication
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stoma Site Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial Thrombosis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coronary Artery Thrombosis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Atelectasis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hiccups
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    9 / 779 (1.16%)
         occurrences causally related to treatment / all
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Respiratory Failure
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Thoracic Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 779 (0.90%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    12 / 779 (1.54%)
         occurrences causally related to treatment / all
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    14 / 779 (1.80%)
         occurrences causally related to treatment / all
    17 / 18
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombotic Microangiopathy
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Posterior Reversible Encephalopathy Syndrome
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    White Matter Lesion
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal Detachment
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    8 / 779 (1.03%)
         occurrences causally related to treatment / all
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal Fistula
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anorectal Ulcer
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    39 / 779 (5.01%)
         occurrences causally related to treatment / all
    42 / 43
         deaths causally related to treatment / all
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterocutaneous Fistula
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Enterovesical Fistula
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fistula Of Small Intestine
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Fistula
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Hypomotility
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Perforation
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gingival Bleeding
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids Thrombosed
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileus Paralytic
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    12 / 779 (1.54%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 2
    Intestinal Perforation
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    1 / 1
    Large Intestine Perforation
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Odynophagia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Rectal Perforation
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Tenesmus
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    9 / 779 (1.16%)
         occurrences causally related to treatment / all
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    4 / 779 (0.51%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Subileus
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 779 (1.28%)
         occurrences causally related to treatment / all
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Cholecystitis
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Jaundice Cholestatic
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Portal Hypertension
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Hydronephrosis
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    5 / 779 (0.64%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Prerenal Failure
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Retention
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Proteinuria
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 779 (0.64%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Abdominal Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Wall Abscess
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Catheter Site Abscess
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device Related Infection
         subjects affected / exposed
    7 / 779 (0.90%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Diabetic Foot Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis Escherichia Coli
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster Meningoencephalitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    5 / 779 (0.64%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Infective Myositis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Klebsiella Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Lung Infection
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Neutropenic Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    2 / 2
    Parainfluenzae Virus Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic Abscess
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Phlebitis Infective
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 779 (1.03%)
         occurrences causally related to treatment / all
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Abscess
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    3 / 779 (0.39%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 779 (0.90%)
         occurrences causally related to treatment / all
    6 / 8
         deaths causally related to treatment / all
    2 / 2
    Septic Shock
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Sinusitis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal Bacteraemia
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    2 / 779 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    5 / 779 (0.64%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 779 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Aflibercept + FOLFIRI (Irinotecan, 5-FU & Leucovorin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    744 / 779 (95.51%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    369 / 779 (47.37%)
         occurrences all number
    557
    Investigations
    Weight Decreased
         subjects affected / exposed
    171 / 779 (21.95%)
         occurrences all number
    185
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    57 / 779 (7.32%)
         occurrences all number
    65
    Dysphonia
         subjects affected / exposed
    131 / 779 (16.82%)
         occurrences all number
    153
    Dyspnoea
         subjects affected / exposed
    62 / 779 (7.96%)
         occurrences all number
    69
    Epistaxis
         subjects affected / exposed
    153 / 779 (19.64%)
         occurrences all number
    193
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    277 / 779 (35.56%)
         occurrences all number
    611
    Nervous system disorders
    Headache
         subjects affected / exposed
    105 / 779 (13.48%)
         occurrences all number
    133
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    192 / 779 (24.65%)
         occurrences all number
    318
    Fatigue
         subjects affected / exposed
    283 / 779 (36.33%)
         occurrences all number
    415
    Pyrexia
         subjects affected / exposed
    87 / 779 (11.17%)
         occurrences all number
    112
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    54 / 779 (6.93%)
         occurrences all number
    61
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    150 / 779 (19.26%)
         occurrences all number
    194
    Abdominal Pain Upper
         subjects affected / exposed
    67 / 779 (8.60%)
         occurrences all number
    77
    Constipation
         subjects affected / exposed
    148 / 779 (19.00%)
         occurrences all number
    180
    Diarrhoea
         subjects affected / exposed
    464 / 779 (59.56%)
         occurrences all number
    1000
    Nausea
         subjects affected / exposed
    337 / 779 (43.26%)
         occurrences all number
    640
    Proctalgia
         subjects affected / exposed
    39 / 779 (5.01%)
         occurrences all number
    44
    Stomatitis
         subjects affected / exposed
    329 / 779 (42.23%)
         occurrences all number
    570
    Vomiting
         subjects affected / exposed
    190 / 779 (24.39%)
         occurrences all number
    311
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    102 / 779 (13.09%)
         occurrences all number
    133
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    143 / 779 (18.36%)
         occurrences all number
    144
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    79 / 779 (10.14%)
         occurrences all number
    89
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    47 / 779 (6.03%)
         occurrences all number
    50
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    206 / 779 (26.44%)
         occurrences all number
    263

    More information

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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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