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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GS-5745 Combined with mFOLFOX6 as First Line Treatment in Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

    Summary
    EudraCT number
    		 2015-001526-42
    Trial protocol
    		 GB   PL   DE   HU   ES   RO   CZ   FR   BE   IT  
    Global end of trial date
    15 May 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 May 2020
    First version publication date
    01 May 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Clarified the meaning of "Not Permitted" category in the Race and Ethinicity Baseline Measures.

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-296-1080
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02545504
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences , GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center , Gilead Sciences , GileadClinicalTrials@gilead.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
    15 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of andecaliximab (GS-5745) versus placebo in combination with modified fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (OXA) (mFOLFOX6) as measured by overall survival.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    Turkey: 35
    Country: Number of subjects enrolled
    Australia: 31
    Country: Number of subjects enrolled
    Chile: 26
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Colombia: 11
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Romania: 28
    Country: Number of subjects enrolled
    Spain: 55
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 26
    Worldwide total number of subjects
    432
    EEA total number of subjects
    215
    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)
    265
    From 65 to 84 years
    166
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Australia, Europe, Chile, Colombia, Peru, Turkey, and the United States. The first participant was screened on 13 October 2015. The last study visit occurred on 15 May 2019.

    Pre-assignment
    Screening details
    		 635 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Andecaliximab + mFOLFOX6
    Arm description
    		 Participants were randomized to receive andecaliximab 800 mg intravenous (IV) plus mFOLFOX6 [leucovorin (LV)+5-fluorouracil (5-FU) + oxaliplatin (OXA)] IV as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by andecaliximab 800 mg IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 135.4 weeks at the time of final analysis for the endpoints and up to 161.7 weeks to the end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Andecaliximab
    Investigational medicinal product code
    Other name
    GS-5745
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg administered on Days 1 and 15 of each 28-day treatment cycle

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously per standard of care on Days 1 and 15 of each treatment cycle

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously per standard of care on Days 1 and 15 of each treatment cycle

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously per standard of care on Days 1 and 15 of each treatment cycle

    Arm title
    		 Placebo + mFOLFOX6
    Arm description
    		 Participants were randomized to receive placebo IV plus mFOLFOX6 (LV+5-FU+OXA) as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by placebo IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 99.7 weeks at the time of final analysis for the endpoints and up to 112.3 weeks to the end of study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously on Days 1 and 15 of each treatment cycle

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously per standard of care on Days 1 and 15 of each treatment cycle

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously per standard of care on Days 1 and 15 of each treatment cycle

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously per standard of care on Days 1 and 15 of each treatment cycle

    Number of subjects in period 1
    		Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6
    Started
    218
    214
    Completed
    0
    0
    Not completed
    218
    214
         Death
    174
    168
         Unknown reason
    30
    32
         Withdrew consent
    9
    11
         Investigator's discretion
    3
    1
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Andecaliximab + mFOLFOX6
    Reporting group description
    		 Participants were randomized to receive andecaliximab 800 mg intravenous (IV) plus mFOLFOX6 [leucovorin (LV)+5-fluorouracil (5-FU) + oxaliplatin (OXA)] IV as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by andecaliximab 800 mg IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 135.4 weeks at the time of final analysis for the endpoints and up to 161.7 weeks to the end of study.

    Reporting group title
    Placebo + mFOLFOX6
    Reporting group description
    		 Participants were randomized to receive placebo IV plus mFOLFOX6 (LV+5-FU+OXA) as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by placebo IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 99.7 weeks at the time of final analysis for the endpoints and up to 112.3 weeks to the end of study.

    Reporting group values
    		 Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6 Total
    Number of subjects
    		 218 214 432
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60 ( 11.9 ) 61 ( 11.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 50 61 111
        Male
    		 168 153 321
    Ethnicity
    Not Permitted = local regulators did not allow collection of race or ethnicity information.
    Units: Subjects
        Hispanic or Latino
    		 38 32 70
        Not Hispanic or Latino
    		 170 173 343
        Not Permitted
    		 10 9 19
    Race
    Not Permitted = local regulators did not allow collection of race or ethnicity information.
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 5 5 10
        Black or African American
    		 4 4 8
        White
    		 186 184 370
        Not Permitted
    		 8 6 14
        Other
    		 15 14 29
    Region of Enrollment
    Units: Subjects
        Colombia
    		 5 6 11
        Romania
    		 15 13 28
        Hungary
    		 11 15 26
        United States
    		 47 59 106
        Czechia
    		 10 5 15
        United Kingdom
    		 5 6 11
        Spain
    		 27 28 55
        Turkey
    		 17 18 35
        Belgium
    		 2 3 5
        Poland
    		 13 11 24
        Italy
    		 8 6 14
        Australia
    		 13 18 31
        Chile
    		 15 11 26
        France
    		 10 3 13
        Peru
    		 4 4 8
        Germany
    		 16 8 24
    Type of Cancer
    Units: Subjects
        Gastric
    		 142 143 285
        Gastroesophageal junction
    		 76 71 147

    End points

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    End points reporting groups
    Reporting group title
    Andecaliximab + mFOLFOX6
    Reporting group description
    		 Participants were randomized to receive andecaliximab 800 mg intravenous (IV) plus mFOLFOX6 [leucovorin (LV)+5-fluorouracil (5-FU) + oxaliplatin (OXA)] IV as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by andecaliximab 800 mg IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 135.4 weeks at the time of final analysis for the endpoints and up to 161.7 weeks to the end of study.

    Reporting group title
    Placebo + mFOLFOX6
    Reporting group description
    		 Participants were randomized to receive placebo IV plus mFOLFOX6 (LV+5-FU+OXA) as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by placebo IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 99.7 weeks at the time of final analysis for the endpoints and up to 112.3 weeks to the end of study.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time interval from the date of randomization to death from any cause. The Intent-to-Treat (ITT) Analysis Set included all randomized participants.
    End point type
    Primary
    End point timeframe
    Andecaliximab + mFOLFOX6 median follow-up at the time of final analysis: 19.43 months; Placebo + mFOLFOX6 median follow-up at the time of the final analysis: 19.45 months
    End point values
    		 Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    218
    214
    Units: months
        median (confidence interval 95%)
    12.52 (11.2 to 14.0)
    11.76 (10.3 to 13.5)
    Statistical analysis title
    		 OS: Andecaliximab + mFOLFOX6 vs Placebo + mFOLFOX6
    Statistical analysis description
    The primary and secondary endpoints were tested sequentially in the following gate-keeping order: the primary OS endpoint, then the secondary PFS endpoint, and finally the secondary ORR endpoint.
    Comparison groups
    Andecaliximab + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.5625 [2]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.18
    Notes
    [1] - p-value was stratified by Eastern Cooperative Oncology Group (ECOG) status, geographic region and primary tumor site and Hazard ratio (HR) was stratified by ECOG status, geographic region and primary tumor site with treatment arm as a covariate.
    [2] - The significance level at final analysis was 0.046 (two-sided). Stratum with < 6 participants or no informative event by combined treatment arms was pooled with the smallest adjacent stratum for stratified analyses.

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the interval of time from the date of randomisation to the earlier of the first documentation of definitive disease progression or death from any cause. Participants in the ITT Analysis Set were analysed.
    End point type
    Secondary
    End point timeframe
    Andecaliximab + mFOLFOX6 median follow-up at the time of final analysis: 18.64 months; Placebo + mFOLFOX6 median follow-up at the time of final analysis: 18.74 months
    End point values
    		 Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    218
    214
    Units: months
        median (confidence interval 95%)
    7.46 (7.29 to 8.41)
    7.06 (5.52 to 7.46)
    Statistical analysis title
    		 PFS:Andecaliximab + mFOLFOX6 vs Placebo + mFOLFOX6
    Statistical analysis description
    The primary and secondary endpoints were tested sequentially in the following gate-keeping order: the primary OS endpoint, then the secondary PFS endpoint, and finally the secondary ORR endpoint. PFS was tested only if OS was significant.The P-value is for display only.
    Comparison groups
    Placebo + mFOLFOX6 v Andecaliximab + mFOLFOX6
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1031 [4]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.04
    Notes
    [3] - p-value was stratified by ECOG status,geographic region and primary tumor site and HR was stratified by ECOG status, geographic region and primary tumor site with treatment arm as a covariate.
    [4] - The significance level at final analysis was 0.032 (two-sided). Stratum with < 6 participants or no informative event by combined treatment arms was pooled with the smallest adjacent stratum for stratified analyses.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions and disappearance of all non-target lesions and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants in the ITT Analysis Set were analysed.
    End point type
    Secondary
    End point timeframe
    Up to 135.4 weeks at the time of final analysis
    End point values
    		 Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    218
    214
    Units: percentage of participants
        number (confidence interval 95%)
    50.5 (43.6 to 57.3)
    41.1 (34.5 to 48.0)
    Statistical analysis title
    		 ORR:Andecaliximab + mFOLFOX6 vs Placebo + mFOLFOX6
    Statistical analysis description
    The primary and secondary endpoints were tested sequentially in the following gate-keeping order: the primary OS endpoint, then the secondary PFS endpoint, and finally the secondary ORR endpoint. ORR was tested only if OS and PFS were significant.The P-value is for display only.
    Comparison groups
    Placebo + mFOLFOX6 v Andecaliximab + mFOLFOX6
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0493 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.15
    Notes
    [5] - p-value and Odds Ratio were stratified by ECOG status, geographic region and primary tumor site.
    [6] - The significance level at final analysis was 0.032 (two-sided). Stratum with < 6 participants or no informative event by combined treatment arms was pooled with the smallest adjacent stratum for stratified analyses.
    Statistical analysis title
    		 ORR:Andecaliximab + mFOLFOX6 vs Placebo + mFOLFOX6
    Statistical analysis description
    A Cochran-Mantel-Haenszel Chi-square test for association between treatment and response, after adjusting for stratification factors, was performed to compare the 2 treatment groups. The 2-sided 95% confidence interval (CI) of difference for ORR between the treatment and placebo is calculated based on stratum-adjusted Cochran-Mantel-Haenszel proportion.
    Comparison groups
    Andecaliximab + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 ORR Difference
    Point estimate
    9.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 18.8

    Secondary: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. TEAEs are events in a given study period that meet any of the following criteria: Any AE with onset date of on or after andecalizimab/placebo start date and no later than 30 days after permanent discontinuation of all study treatment (andecaliximab/placebo and chemotherapy) or Any AEs with onset date of on or after the andecaliximab/placebo start date and no later than 55 days after permanent discontinuation of andecaliximab/placebo or AEs leading to discontinuation of andecaliximab/placebo. The Safety Analysis Set included all participants who received at least one dose of andecaliximab/placebo.
    End point type
    Secondary
    End point timeframe
    First dose date up to the last dose date (maximum: 161.7 weeks) plus 30 to 55 days
    End point values
    		 Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    216
    210
    Units: percentage of participants
        number (not applicable)
    99.1
    99.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinically Relevant Treatment-emergent Laboratory Abnormalities

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    End point title
    		 Percentage of Participants With Clinically Relevant Treatment-emergent Laboratory Abnormalities
    End point description
    Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 where 0=None, 1=Mild, 2=Moderate, 3=Severe, 4=Potentially Life Threatening. Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from baseline at any post-baseline time point, up to 30 days after the last dose of all study treatment, or 55 days after the last dose of andecaliximab/placebo for participants who permanently discontinued all study treatments. If the relevant baseline laboratory value is missing, then any abnormality of at least Grade 1 was considered treatment-emergent. Participants in the Safety Analysis Set were analysed.
    End point type
    Secondary
    End point timeframe
    First dose date up to the last dose date (maximum: 161.7 weeks) plus 30 to 55 days
    End point values
    		 Andecaliximab + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    216
    210
    Units: percentage of participants
    number (not applicable)
        Hematology
    94.4
    89.5
        Serum Chemistry
    91.7
    92.9
        Coagulation
    7.4
    3.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to the last dose date (maximum: 161.7 weeks) plus 30 to 55 days
    Adverse event reporting additional description
    Serious Adverse Events and Non-Serious Adverse Events: The Safety Analysis Set included all participants who received at least one dose of andecaliximab/placebo. The Number of Deaths (All-causes): The Intent-to-Treat (ITT) Analysis Set included all randomized participants.(N=218, 214)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo + mFOLFOX6
    Reporting group description
    		 Participants received placebo IV plus mFOLFOX6 (LV+5-FU+OXA) as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by placebo IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 112.3 weeks.

    Reporting group title
    Andecaliximab + mFOLFOX6
    Reporting group description
    		 Participants received andecaliximab 800 mg intravenous (IV) plus mFOLFOX6 [leucovorin (LV)+5-fluorouracil (5-FU) + oxaliplatin (OXA)] IV as per standard of care on Days 1 and 15 of each 28-day treatment cycle during Cycles 1-6, followed by andecaliximab 800 mg IV plus LV+5-FU on Days 1 and 15 during subsequent cycles until disease progression, unacceptable toxicity, consent withdrawal, or the participant's refusal of treatment for up to 161.7 weeks.

    Serious adverse events
    		 Placebo + mFOLFOX6 Andecaliximab + mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    108 / 210 (51.43%)
    103 / 216 (47.69%)
         number of deaths (all causes)
    168
    174
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 210 (0.00%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor venous access
         subjects affected / exposed
    0 / 210 (0.00%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 210 (0.95%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 210 (0.48%)
    4 / 216 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Fatigue
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 210 (1.43%)
    4 / 216 (1.85%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 210 (1.90%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    2 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 210 (0.48%)
    4 / 216 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    13 / 210 (6.19%)
    8 / 216 (3.70%)
         occurrences causally related to treatment / all
    3 / 13
    2 / 8
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 210 (0.48%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occult blood positive
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic ulcer
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 210 (1.43%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiovascular disorder
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 210 (0.95%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Headache
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 210 (0.95%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 210 (2.38%)
    6 / 216 (2.78%)
         occurrences causally related to treatment / all
    4 / 5
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Neutropenia
         subjects affected / exposed
    4 / 210 (1.90%)
    4 / 216 (1.85%)
         occurrences causally related to treatment / all
    6 / 6
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 210 (3.81%)
    7 / 216 (3.24%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 210 (0.95%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 210 (0.95%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 210 (2.38%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    3 / 210 (1.43%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 210 (0.95%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastric stenosis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 210 (1.90%)
    6 / 216 (2.78%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 210 (1.90%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 210 (1.90%)
    4 / 216 (1.85%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    6 / 210 (2.86%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small intestinal obstruction
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 210 (1.90%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    8 / 210 (3.81%)
    11 / 216 (5.09%)
         occurrences causally related to treatment / all
    6 / 12
    7 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute on chronic liver failure
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 210 (0.95%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine flow decreased
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 210 (2.38%)
    7 / 216 (3.24%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pneumonia necrotising
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 210 (1.90%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 210 (0.48%)
    4 / 216 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 210 (1.43%)
    3 / 216 (1.39%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + mFOLFOX6 Andecaliximab + mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    203 / 210 (96.67%)
    209 / 216 (96.76%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 210 (5.71%)
    11 / 216 (5.09%)
         occurrences all number
    13
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 210 (5.24%)
    13 / 216 (6.02%)
         occurrences all number
    13
    23
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 210 (4.29%)
    15 / 216 (6.94%)
         occurrences all number
    11
    19
    Neutrophil count decreased
         subjects affected / exposed
    25 / 210 (11.90%)
    30 / 216 (13.89%)
         occurrences all number
    37
    47
    Platelet count decreased
         subjects affected / exposed
    17 / 210 (8.10%)
    19 / 216 (8.80%)
         occurrences all number
    26
    32
    Weight decreased
         subjects affected / exposed
    23 / 210 (10.95%)
    29 / 216 (13.43%)
         occurrences all number
    25
    30
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 210 (5.24%)
    9 / 216 (4.17%)
         occurrences all number
    17
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    26 / 210 (12.38%)
    19 / 216 (8.80%)
         occurrences all number
    35
    22
    Dysgeusia
         subjects affected / exposed
    15 / 210 (7.14%)
    21 / 216 (9.72%)
         occurrences all number
    16
    30
    Dysaesthesia
         subjects affected / exposed
    12 / 210 (5.71%)
    15 / 216 (6.94%)
         occurrences all number
    26
    26
    Headache
         subjects affected / exposed
    15 / 210 (7.14%)
    18 / 216 (8.33%)
         occurrences all number
    17
    32
    Neuropathy peripheral
         subjects affected / exposed
    21 / 210 (10.00%)
    28 / 216 (12.96%)
         occurrences all number
    23
    41
    Neurotoxicity
         subjects affected / exposed
    11 / 210 (5.24%)
    10 / 216 (4.63%)
         occurrences all number
    19
    18
    Paraesthesia
         subjects affected / exposed
    24 / 210 (11.43%)
    27 / 216 (12.50%)
         occurrences all number
    31
    31
    Peripheral sensory neuropathy
         subjects affected / exposed
    72 / 210 (34.29%)
    73 / 216 (33.80%)
         occurrences all number
    105
    124
    Taste disorder
         subjects affected / exposed
    11 / 210 (5.24%)
    7 / 216 (3.24%)
         occurrences all number
    11
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    62 / 210 (29.52%)
    61 / 216 (28.24%)
         occurrences all number
    76
    70
    Neutropenia
         subjects affected / exposed
    73 / 210 (34.76%)
    76 / 216 (35.19%)
         occurrences all number
    127
    141
    Thrombocytopenia
         subjects affected / exposed
    32 / 210 (15.24%)
    38 / 216 (17.59%)
         occurrences all number
    60
    55
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    52 / 210 (24.76%)
    62 / 216 (28.70%)
         occurrences all number
    78
    144
    Chest pain
         subjects affected / exposed
    11 / 210 (5.24%)
    7 / 216 (3.24%)
         occurrences all number
    13
    8
    Fatigue
         subjects affected / exposed
    72 / 210 (34.29%)
    79 / 216 (36.57%)
         occurrences all number
    108
    124
    Mucosal inflammation
         subjects affected / exposed
    26 / 210 (12.38%)
    25 / 216 (11.57%)
         occurrences all number
    49
    32
    Oedema peripheral
         subjects affected / exposed
    20 / 210 (9.52%)
    18 / 216 (8.33%)
         occurrences all number
    23
    20
    Pyrexia
         subjects affected / exposed
    18 / 210 (8.57%)
    25 / 216 (11.57%)
         occurrences all number
    21
    32
    Temperature intolerance
         subjects affected / exposed
    12 / 210 (5.71%)
    12 / 216 (5.56%)
         occurrences all number
    19
    18
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    14 / 210 (6.67%)
    14 / 216 (6.48%)
         occurrences all number
    14
    16
    Abdominal pain
         subjects affected / exposed
    37 / 210 (17.62%)
    41 / 216 (18.98%)
         occurrences all number
    48
    65
    Abdominal pain upper
         subjects affected / exposed
    26 / 210 (12.38%)
    19 / 216 (8.80%)
         occurrences all number
    34
    26
    Ascites
         subjects affected / exposed
    13 / 210 (6.19%)
    11 / 216 (5.09%)
         occurrences all number
    14
    11
    Constipation
         subjects affected / exposed
    61 / 210 (29.05%)
    61 / 216 (28.24%)
         occurrences all number
    77
    84
    Diarrhoea
         subjects affected / exposed
    88 / 210 (41.90%)
    87 / 216 (40.28%)
         occurrences all number
    152
    176
    Dry mouth
         subjects affected / exposed
    12 / 210 (5.71%)
    8 / 216 (3.70%)
         occurrences all number
    15
    8
    Dyspepsia
         subjects affected / exposed
    8 / 210 (3.81%)
    20 / 216 (9.26%)
         occurrences all number
    8
    20
    Dysphagia
         subjects affected / exposed
    19 / 210 (9.05%)
    21 / 216 (9.72%)
         occurrences all number
    25
    26
    Flatulence
         subjects affected / exposed
    10 / 210 (4.76%)
    11 / 216 (5.09%)
         occurrences all number
    11
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    14 / 210 (6.67%)
    9 / 216 (4.17%)
         occurrences all number
    14
    11
    Nausea
         subjects affected / exposed
    118 / 210 (56.19%)
    106 / 216 (49.07%)
         occurrences all number
    226
    223
    Stomatitis
         subjects affected / exposed
    21 / 210 (10.00%)
    24 / 216 (11.11%)
         occurrences all number
    33
    30
    Vomiting
         subjects affected / exposed
    62 / 210 (29.52%)
    63 / 216 (29.17%)
         occurrences all number
    118
    125
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 210 (10.95%)
    25 / 216 (11.57%)
         occurrences all number
    27
    28
    Dyspnoea
         subjects affected / exposed
    22 / 210 (10.48%)
    20 / 216 (9.26%)
         occurrences all number
    26
    31
    Epistaxis
         subjects affected / exposed
    19 / 210 (9.05%)
    16 / 216 (7.41%)
         occurrences all number
    20
    17
    Hiccups
         subjects affected / exposed
    9 / 210 (4.29%)
    11 / 216 (5.09%)
         occurrences all number
    10
    13
    Pulmonary embolism
         subjects affected / exposed
    12 / 210 (5.71%)
    10 / 216 (4.63%)
         occurrences all number
    13
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    16 / 210 (7.62%)
    14 / 216 (6.48%)
         occurrences all number
    16
    15
    Rash
         subjects affected / exposed
    11 / 210 (5.24%)
    13 / 216 (6.02%)
         occurrences all number
    14
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    22 / 210 (10.48%)
    27 / 216 (12.50%)
         occurrences all number
    26
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 210 (4.76%)
    14 / 216 (6.48%)
         occurrences all number
    12
    14
    Back pain
         subjects affected / exposed
    20 / 210 (9.52%)
    25 / 216 (11.57%)
         occurrences all number
    21
    28
    Musculoskeletal pain
         subjects affected / exposed
    4 / 210 (1.90%)
    12 / 216 (5.56%)
         occurrences all number
    4
    15
    Myalgia
         subjects affected / exposed
    4 / 210 (1.90%)
    11 / 216 (5.09%)
         occurrences all number
    4
    11
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 210 (3.81%)
    16 / 216 (7.41%)
         occurrences all number
    12
    18
    Urinary tract infection
         subjects affected / exposed
    11 / 210 (5.24%)
    16 / 216 (7.41%)
         occurrences all number
    16
    23
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    72 / 210 (34.29%)
    63 / 216 (29.17%)
         occurrences all number
    93
    106
    Dehydration
         subjects affected / exposed
    16 / 210 (7.62%)
    16 / 216 (7.41%)
         occurrences all number
    20
    17
    Hyperglycaemia
         subjects affected / exposed
    6 / 210 (2.86%)
    13 / 216 (6.02%)
         occurrences all number
    8
    20
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 210 (3.81%)
    12 / 216 (5.56%)
         occurrences all number
    8
    12
    Hypokalaemia
         subjects affected / exposed
    22 / 210 (10.48%)
    28 / 216 (12.96%)
         occurrences all number
    29
    43

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2015
    Amendment 1: 1. The study phase was changed from Phase 2 to Phase 3. 2. References to enrollment in relation to study procedures was replaced with randomization.
    17 Aug 2015
    Amendment 2: 1. The details on the preparation of GS-5745/placebo (study drug) were removed from the protocol. Additional testing to determine a longer duration of stability was conducted and the preparation instructions provided in the protocol were changed. Detailed study drug preparation instructions were provided separately in a pharmacy manual. 2. To correct errors and inconsistencies in the protocol.
    14 Dec 2015
    Amendment 3: 1. An additional 55-day phone follow-up was added to the original 30 day safety follow up in multiple sections.
    22 Jun 2016
    Amendment 4: 1. Implemented the updated prescribing information for oxaliplatin in the global protocol. These changes were previously implemented in a French specific protocol amendment (version 3.1). 2. Added an exploratory objective and endpoints for the data collected from patient-reported outcomes. 3. Clarified the dosing requirements for mFOLFOX6 and GS-5745/placebo. 4. Corrected the timing for the coagulation tests when determining eligibility. 5. Changed the p-value from 2-sided to 1-sided in the statistical methods for consistency. 6. Clarified procedures for withdrawing consent. 7. Clarified management of toxicities attributed to GS-745/placebo. 8. Added details on the testing for efficacy endpoints for reference. 9. Corrected minor errors and inconsistencies throughout the protocol.
    14 Dec 2016
    Amendment 5: 1. Changed the inclusion criterion on creatinine clearance to reflect the current safety profile of GS-5745 and the oxaliplatin label. 2. Clarified the exclusion criterion on radiotherapy. 3. Revised the instructions on cardiac monitoring after oxaliplatin dosing to reflect each country’s standard practice by following the prescribing information/summary of product characteristics (SmPC) for oxaliplatin approved at the local country level. 4. Clarified the timing of the first safety review by the data monitoring committee (DMC). 5. Corrected the duration of the collection of AEs and the timing of the scheduling of the 30- and 55-Day Safety Follow Up visits. 6. Provided the flexibility to follow institutional guidance/practices to calculate body surface area (BSA). 7. Added an anti-GS-5745 antibody sample collection time point at the 30-Day Safety Follow Up visit. 8. Increased the window for using CT/MRI scans obtain during standard of care for screening. 9. Corrected minor errors and inconsistencies throughout the protocol.
    06 Mar 2017
    Amendment 6: 1. Updated the futility interim analysis. 2. Provided further clarifications on guidelines for dose interruption and reduction. 3. Corrected minor errors and inconsistencies throughout the protocol.

    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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