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    Clinical Trial Results:
    A Randomized, Multicenter, Open-label, Phase 3 Study to Compare the Efficacy and Safety of Panitumumab and Cetuximab in Subjects with Previously Treated, Wild-type KRAS, Metastatic Colorectal Cancer

    Summary
    EudraCT number
    2009-010715-32
    Trial protocol
    LV   FR   LT   CZ   SE   BE   SK   IT   NL   GB   BG  
    Global end of trial date
    03 Mar 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Mar 2018
    First version publication date
    03 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20080763
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01001377
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    18 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the effect of panitumumab versus cetuximab on overall survival (OS) for chemorefractory metastatic colorectal cancer (mCRC) among patients with wild-type Kirsten rat Sarcoma-2 virus (KRAS) tumors.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The protocol and amendment were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB)at each center. The investigator or a designee was to obtain written informed consent from all subjects or legally acceptable representatives after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures were conducted or investigational products were administered.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Feb 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 105
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Sweden: 29
    Country: Number of subjects enrolled
    United Kingdom: 82
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    China: 100
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Hong Kong: 23
    Country: Number of subjects enrolled
    India: 50
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 210
    Country: Number of subjects enrolled
    Latvia: 13
    Country: Number of subjects enrolled
    Lithuania: 24
    Country: Number of subjects enrolled
    Malaysia: 21
    Country: Number of subjects enrolled
    Peru: 11
    Country: Number of subjects enrolled
    Philippines: 8
    Country: Number of subjects enrolled
    Poland: 64
    Country: Number of subjects enrolled
    Russian Federation: 80
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    South Africa: 23
    Country: Number of subjects enrolled
    Taiwan: 25
    Worldwide total number of subjects
    1010
    EEA total number of subjects
    312
    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)
    657
    From 65 to 84 years
    350
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 1010 subjects with wild-type KRAS exon 2 mCRC were randomized into the global protocol from 133 study centers in 27 countries between 02 February 2010 and 19 July 2012.

    Pre-assignment
    Screening details
    Enrollment was stratified by geographic region (North America, Western Europe, and Australia versus the rest of the world) and Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2) and randomized in a 1:1 ratio to receive either intravenous (IV) panitumumab or IV cetuximab.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cetuximab
    Arm description
    Cetuximab 400 mg/m² as an initial dose, followed by 250 mg/m² intravenously (IV) every 7 days until disease progression, intolerability, withdrawal of consent, or death.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered by IV infusion on day 1 of each 7-day cycle. The initial loading dose of cetuximab was 400 mg/m². All subsequent doses were 250 mg/m².

    Arm title
    Panitumumab
    Arm description
    Panitumumab 6 mg/kg IV every 14 days until disease progression, intolerability, withdrawal of consent, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Panitumumab
    Investigational medicinal product code
    Other name
    Vectibix
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Panitumumab was administered by IV infusion at a dose of 6 mg/kg on day 1 of every 14-day cycle.

    Number of subjects in period 1
    Cetuximab Panitumumab
    Started
    504
    506
    Received Treatment
    500
    499
    Completed
    0
    2
    Not completed
    504
    504
         Death
    454
    448
         Administrative decision
    14
    15
         Ineligibility determined
    2
    -
         Consent withdrawn by subject
    19
    20
         Lost to follow-up
    15
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cetuximab
    Reporting group description
    Cetuximab 400 mg/m² as an initial dose, followed by 250 mg/m² intravenously (IV) every 7 days until disease progression, intolerability, withdrawal of consent, or death.

    Reporting group title
    Panitumumab
    Reporting group description
    Panitumumab 6 mg/kg IV every 14 days until disease progression, intolerability, withdrawal of consent, or death.

    Reporting group values
    Cetuximab Panitumumab Total
    Number of subjects
    504 506 1010
    Age Categorical
    Units: Subjects
        < 65 years
    319 338 657
        ≥ 65 years
    185 168 353
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.2 ± 11.2 59.6 ± 10.9 -
    Gender Categorical
    Units: Subjects
        Female
    183 187 370
        Male
    321 319 640
    Race
    Units: Subjects
        Asian
    230 225 455
        Black or African American
    4 2 6
        Hispanic or Latino
    7 6 13
        Japanese
    0 1 1
        Other
    3 2 5
        White or Caucasian
    260 270 530
    Geographic Region
    Units: Subjects
        North America, Western Europe and Australia
    158 158 316
        Rest of the world
    346 348 694
    Eastern Cooperative Oncology Group (ECOG) performance status
    0 = Fully active, able to carry on all pre-disease performance without restriction. 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, ie, light housework or office work. 2 = Ambulatory and capable of all self-care but unable to carry out any work. activities. Up and about > 50% of waking hours. 3 = Capable of only limited self-care, confined to a bed or chair > 50% of waking hours. 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 = Dead.
    Units: Subjects
        Grade 0
    165 155 320
        Grade 1
    299 309 608
        Grade 2
    40 42 82

    End points

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    End points reporting groups
    Reporting group title
    Cetuximab
    Reporting group description
    Cetuximab 400 mg/m² as an initial dose, followed by 250 mg/m² intravenously (IV) every 7 days until disease progression, intolerability, withdrawal of consent, or death.

    Reporting group title
    Panitumumab
    Reporting group description
    Panitumumab 6 mg/kg IV every 14 days until disease progression, intolerability, withdrawal of consent, or death.

    Primary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival (OS) is the time from the date of randomization until the date of death. Participants who had not died by the analysis data cut-off date were censored at their last contact date. The analysis was conducted using the primary analysis set, which included all participants who were randomized and who received at least 1 dose of panitumumab or cetuximab; analyzed according to randomized treatment arm.
    End point type
    Primary
    End point timeframe
    From randomization until the final analysis data cut-off date of 18 July 2014. Median time on study was 41 weeks, maximum time on study was 214 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    500
    499
    Units: months
        median (confidence interval 95%)
    9.9 (9.0 to 10.8)
    10.2 (9.4 to 11.4)
    Statistical analysis title
    Primary Analysis of Overall Survival
    Statistical analysis description
    The hazard ratio and its corresponding 95% CI were estimated from a Cox proportional hazards model stratified by the randomization factors (geographic region [North America, western Europe and Australia vs rest of world] and ECOG performance status [0 or 1 vs 2]). The hazard ratio is presented as panitumumab : cetuximab. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab relative to cetuximab.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.0002
    Method
    Asymptotic standard normal test
    Parameter type
    Cox proportional hazard
    Point estimate
    0.938
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.823
         upper limit
    1.071
    Notes
    [1] - A synthesis approach with an asymptotic standard normal test statistic based on the logarithm of the hazard ratio was used to test the hypothesis that panitumumab is noninferior to cetuximab for OS (ie, that panitumumab retains at least 50% of the OS benefit of cetuximab relative to BSC). The OS noninferiority hypothesis based on an asymptotic normal score was tested at a 1-sided 2.5% significance level. A value < -1.96 indicates non-inferiority at a significance level of 1-sided 0.025.

    Secondary: Progression-free Survival

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    End point title
    Progression-free Survival
    End point description
    Progression free survival (PFS) is the time from the date of randomization to the date of disease progression per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or death. Participants alive and not meeting criteria for progression by the analysis data cut-off date were censored at their last evaluable disease assessment date. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study based on all target lesions recorded since the treatment started (the sum must also demonstrate an absolute increase of at least 5 mm), or unequivocal progression of existing non-target lesions, or any new lesions. The analysis was conducted using the primary analysis set.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 18 July 2014. Median time on study was 41 weeks, maximum time on study was 214 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    500
    499
    Units: months
        median (confidence interval 95%)
    4.4 (3.2 to 4.8)
    4.2 (3.2 to 4.8)
    Statistical analysis title
    Analysis of Progression-Free Survival
    Statistical analysis description
    The hazard ratio and its corresponding 95% CI were estimated from a Cox proportional hazards model stratified by the randomization factors (geographic region [North America, western Europe and Australia vs rest of world] and ECOG performance status [0 or 1 vs 2]). The hazard ratio is presented as panitumumab : cetuximab. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab relative to cetuximab.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.984
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.867
         upper limit
    1.117

    Secondary: Objective Response

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    End point title
    Objective Response
    End point description
    Assessments are based on the investigator's review of scans using modified RECIST v1.1. Objective response is defined as either a complete response (CR) or partial response (PR). Participants who did not meet the criteria for an objective response by the analysis cut-off date were considered non-responders. CR: Disappearance of all target and non-target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, and no new lesions. PR: Disappearance of all target lesions, persistence of one or more non-target lesions not qualifying for either CR or progressive disease, or, at least a 30% decrease in the size of target lesions with no unequivocal progression of existing non-target lesions and no new lesions. Objective response was analyzed using the tumor response analysis set, which includes participants in the primary analysis set with at least 1 baseline unidimensionally measurable lesion per RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 18 July 2014. Median time on study was 41 weeks, maximum time on study was 214 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    485
    486
    Units: percentage of participants
        number (confidence interval 95%)
    19.79 (16.34 to 23.62)
    22.02 (18.41 to 25.97)
    Statistical analysis title
    Analysis of Objective Response
    Statistical analysis description
    The common treatment odds ratio stratified by geographic region (North America, western Europe and Australia vs rest of world) and ECOG performance status (0 or 1 vs 2). The odds ratio is defined as the odds of having an objective response (CR or PR) in the panitumumab arm relative to the odds in the cetuximab arm.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    971
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.58

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of response (DOR), calculated only for those participants with an objective response, is the time from first objective response to disease progression per the RECIST v1.1 or death. Participants not meeting criteria for progression or who died by the analysis data cutoff date were censored at their last evaluable disease assessment date.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 18 July 2014. Median time on study was 41 weeks, maximum time on study was 214 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    96
    107
    Units: months
        median (confidence interval 95%)
    5.4 (3.9 to 5.5)
    3.8 (3.7 to 4.8)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response (TTR), calculated for those participants with an objective response, is defined as the time from the randomization date to the date of first objective response.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 18 July 2014. Median time on study was 41 weeks, maximum time on study was 214 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    96
    107
    Units: months
        median (inter-quartile range (Q1-Q3))
    2.56 (1.23 to 3.07)
    1.48 (1.18 to 3.02)
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure

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    End point title
    Time to Treatment Failure
    End point description
    Time to treatment failure (TTF) is the time from the randomization date to the date that the decision was made to end the treatment period for any reason; participants who remained in the treatment period at the time of analysis were censored at the date of the last on-study assessment. The analysis was conducted using the primary analysis set.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 18 July 2014. Median time on study was 41 weeks, maximum time on study was 214 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    500
    499
    Units: months
        median (confidence interval 95%)
    3.3 (3.2 to 3.9)
    3.4 (3.2 to 4.6)
    Statistical analysis title
    Analysis of Time to Treatment Failure
    Statistical analysis description
    The hazard ratio and its corresponding 95% CI were estimated from a Cox proportional hazards model stratified by the randomization factors (geographic region [North America, western Europe and Australia vs rest of world] and ECOG performance status [0 or 1 vs 2]). The hazard ratio is presented as panitumumab : cetuximab. A value < 1.0 indicates a lower average event rate and longer time to event for panitumumab relative to cetuximab.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    999
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.982
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.867
         upper limit
    1.113

    Secondary: Change From Baseline in EuroQOL 5 Dimension (EQ-5D) Health State Index Score

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    End point title
    Change From Baseline in EuroQOL 5 Dimension (EQ-5D) Health State Index Score
    End point description
    The EQ-5D is a generic measure of health outcome. The health state index measures 5 health dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, using 3 levels of response to reflect degree of problems: no problem (1), some problem (2) and extreme problems (3). The health states for each respondent are converted into a single index number using a specified set of weights. Resulting scores can range from 1.0 and –0.594. A higher score indicates a more preferred health status with 1.0 representing perfect health and 0 representing death. Negative scores are possible and represent health states regarded as less preferable than death (0). The analysis was conducted using the patient reported outcomes (PRO) analysis set, which included all participants in the primary analysis set who had a baseline and at least one follow-up PRO assessment prior to clinical or objective disease progression per RECIST v1.1. Participants with available data are included.
    End point type
    Secondary
    End point timeframe
    From Study Day 1 through the last day of treatment or disease progression, up to Week 85.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    150
    143
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -0.0341 (-0.0806 to 0.0123)
    -0.0216 (-0.0691 to 0.0260)
    Statistical analysis title
    Analysis of EQ-5D Health State Index Score
    Statistical analysis description
    Repeated measures mixed model includes treatment, geographic region, ECOG score, assessment week, and treatment by assessment week interaction as fixed effects, and subjects a random effect. An unstructured covariance matrix is used in the mixed model. A positive difference between the treatment groups favors the panitumumab group.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    0.0126
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0353
         upper limit
    0.0605

    Secondary: Change From Baseline in EuroQOL 5 Dimension (EQ-5D) Visual Analog Scale (VAS)

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    End point title
    Change From Baseline in EuroQOL 5 Dimension (EQ-5D) Visual Analog Scale (VAS)
    End point description
    The EQ-5D is a standardized instrument for use as a generic measure of health outcome. The VAS asks respondents to rate their present health status on a scale from 0 to 100, with 0 labeled as “Worst imaginable health state” and 100 labeled as “Best imaginable health state.” The VAS score is determined by observing the point at which the participant's hand drawn line intersects the scale. The analysis was conducted using the patient reported outcomes (PRO) analysis set with available data.
    End point type
    Secondary
    End point timeframe
    From Study Day 1 through the last day of treatment or disease progression, up to Week 85.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    149
    142
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    3.9782 (0.8842 to 7.0722)
    2.3037 (-0.8532 to 5.4605)
    Statistical analysis title
    Analysis of EQ-5D Visual Analog Scale
    Statistical analysis description
    Repeated measures mixed model includes treatment, geographic region, ECOG score, assessment week, and treatment by assessment week interaction as fixed effects, and subjects a random effect. An unstructured covariance matrix is used in the mixed model. A positive difference between the treatment groups favors the panitumumab group.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1.6745
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.9331
         upper limit
    1.5841

    Secondary: Change From Baseline in National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Colorectal Symptom Index (NCCN FCSI ) Symptoms Score

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    End point title
    Change From Baseline in National Comprehensive Cancer Network Functional Assessment of Cancer Therapy Colorectal Symptom Index (NCCN FCSI ) Symptoms Score
    End point description
    The FCSI consists of 9 questions comprising the most important symptoms associated with colorectal cancer, including energy, pain, weight, diarrhea, nausea, swelling or cramps in the stomach area, appetite, ability to enjoy life, and overall quality of life. The 9 questions are combined in three algorithms to provide information for 3 domains: colorectal cancer symptoms, physical well-being, and functional well-being. Each of the 9 items are scored from “0” to “4” representing “Not at All” through to “Very Much True”. The raw score for all items is transformed to a 0-100 scale, and the average for each of the 3 subscales is calculated; high scores illustrate an improved state (e.g. able to enjoy life more). The analysis was conducted using the patient reported outcomes (PRO) analysis set with available data.
    End point type
    Secondary
    End point timeframe
    From Study Day 1 through the last day of treatment or disease progression, up to Week 85.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    151
    142
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    2.0101 (-1.1477 to 5.1679)
    3.0473 (-0.1782 to 6.2728)
    Statistical analysis title
    Analysis of NCCN FCSI Symptoms Score
    Statistical analysis description
    Repeated measures mixed model includes treatment, geographic region, ECOG score, assessment week, and treatment by assessment week interaction as fixed effects, and subjects a random effect. An unstructured covariance matrix is used in the mixed model. A positive difference between the treatment groups favors the panitumumab group.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    1.0372
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3267
         upper limit
    4.401

    Secondary: Change From Baseline in NCCN FCSI Physical Well-being Scale Score

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    End point title
    Change From Baseline in NCCN FCSI Physical Well-being Scale Score
    End point description
    The FCSI consists of 9 questions comprising the most important symptoms associated with colorectal cancer, including energy, pain, weight, diarrhea, nausea, swelling or cramps in the stomach area, appetite, ability to enjoy life, and overall quality of life. The 9 questions are combined in three algorithms to provide information for 3 domains: colorectal cancer symptoms, physical well-being, and functional well-being. Each of the 9 items are scored from "0" to "4" representing "Not at All" through to "Very Much True". The raw score for all items is transformed to a 0-100 scale, and the average for each of the 3 subscales is calculated; high scores illustrate an improved state (e.g. able to enjoy life more). The analysis was conducted using the patient reported outcomes (PRO) analysis set with available data.
    End point type
    Secondary
    End point timeframe
    From Study Day 1 through the last day of treatment or disease progression, up to Week 85.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    150
    142
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    1.8778 (-1.5524 to 5.3080)
    2.4614 (-1.0442 to 5.9670)
    Statistical analysis title
    Analysis of NCCN FCSI Physical Well-being Scale
    Statistical analysis description
    Repeated measures mixed model includes treatment, geographic region, ECOG score, assessment week, and treatment by assessment week interaction as fixed effects, and subjects a random effect. An unstructured covariance matrix is used in the mixed model. A positive difference between the treatment groups favors the panitumumab group.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    0.5836
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.0269
         upper limit
    4.1941

    Secondary: Change From Baseline in NCCN FCSI Functional Well-being Scale Score

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    End point title
    Change From Baseline in NCCN FCSI Functional Well-being Scale Score
    End point description
    The FCSI consists of 9 questions comprising the most important symptoms associated with colorectal cancer, including energy, pain, weight, diarrhea, nausea, swelling or cramps in the stomach area, appetite, ability to enjoy life, and overall quality of life. The 9 questions are combined in three algorithms to provide information for 3 domains: colorectal cancer symptoms, physical well-being, and functional well-being. Each of the 9 items are scored from “0” to “4” representing “Not at All” through to “Very Much True”. The raw score for all items is transformed to a 0-100 scale, and the average for each of the 3 subscales is calculated; high scores illustrate an improved state (e.g. able to enjoy life more). The analysis was conducted using the patient reported outcomes (PRO) analysis set with available data.
    End point type
    Secondary
    End point timeframe
    From Study Day 1 through the last day of treatment or disease progression, up to Week 85.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    152
    143
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    1.3567 (-4.1564 to 6.8697)
    1.1569 (-4.4887 to 6.8025)
    Statistical analysis title
    Anlaysis of NCCN FCSI Functional Well-being Scale
    Statistical analysis description
    Repeated measures mixed model includes treatment, geographic region, ECOG score, assessment week, and treatment by assessment week interaction as fixed effects, and subjects a random effect. An unstructured covariance matrix is used in the mixed model. A positive difference between the treatment groups favors the panitumumab group.
    Comparison groups
    Cetuximab v Panitumumab
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.1998
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.0093
         upper limit
    5.6098

    Secondary: Number of Participants With Adverse Events (AEs)

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    End point title
    Number of Participants With Adverse Events (AEs)
    End point description
    Serious adverse events include any event that is fatal, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or other significant medical hazard. Treatment-related AEs are those the investigator considered as a reasonable possibility to have been caused by study drug. The safety analysis set included all randomized participants who received at least 1 dose of study medication. Five participants who received the incorrect study medication (4 assigned to panitumumab but received cetuximab and 1 assigned to cetuximab but received panitumumab) were included in different treatment arms for safety analyses.
    End point type
    Secondary
    End point timeframe
    From the day of the first dose of study therapy through 30 days after the last dose. Median duration of treatment was 14 weeks.
    End point values
    Cetuximab Panitumumab
    Number of subjects analysed
    503
    496
    Units: participants
        Any adverse event (AE)
    494
    487
        Serious adverse events
    171
    151
        AEs leading to discontinuation of study drug
    62
    69
        Treatment-related adverse events (TRAE)
    459
    438
        Treatment-related serious adverse events
    22
    24
        TRAEs leading to discontinuation of study drug
    15
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the day of the first dose of study therapy through 30 days after the last dose. Median duration of treatment was 14 weeks.
    Adverse event reporting additional description
    The safety analysis set included all randomized participants who received at least 1 dose of study medication. Five participants who received the incorrect study medication (4 assigned to panitumumab but received cetuximab and 1 assigned to cetuximab but received panitumumab) were included in different treatment arms for safety analyses.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Cetuximab
    Reporting group description
    Cetuximab 400 mg/m² as an initial dose, followed by 250 mg/m² intravenously (IV) every 7 days until disease progression, intolerability, withdrawal of consent, or death.

    Reporting group title
    Panitumumab
    Reporting group description
    Panitumumab 6 mg/kg IV every 14 days until disease progression, intolerability, withdrawal of consent, or death.

    Serious adverse events
    Cetuximab Panitumumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    171 / 503 (34.00%)
    151 / 496 (30.44%)
         number of deaths (all causes)
    50
    29
         number of deaths resulting from adverse events
    Vascular disorders
    Artery dissection
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central venous catheterisation
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophorectomy bilateral
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colon cancer
         subjects affected / exposed
    4 / 503 (0.80%)
    5 / 496 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Colon cancer metastatic
         subjects affected / exposed
    6 / 503 (1.19%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 6
    0 / 4
    Colorectal cancer
         subjects affected / exposed
    10 / 503 (1.99%)
    6 / 496 (1.21%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 9
    0 / 4
    Colorectal cancer metastatic
         subjects affected / exposed
    14 / 503 (2.78%)
    7 / 496 (1.41%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 7
         deaths causally related to treatment / all
    0 / 12
    0 / 7
    Infected neoplasm
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 503 (0.40%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to ovary
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour thrombosis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    3 / 503 (0.60%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 503 (0.40%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 503 (0.80%)
    6 / 496 (1.21%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 503 (0.80%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 503 (0.40%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 503 (0.40%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 503 (1.59%)
    3 / 496 (0.60%)
         occurrences causally related to treatment / all
    1 / 10
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema genital
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 503 (0.40%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         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 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 503 (1.39%)
    3 / 496 (0.60%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 503 (0.60%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 503 (0.60%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 503 (0.60%)
    6 / 496 (1.21%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (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
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 503 (0.80%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal mass
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    13 / 503 (2.58%)
    10 / 496 (2.02%)
         occurrences causally related to treatment / all
    2 / 14
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 503 (0.40%)
    3 / 496 (0.60%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    5 / 503 (0.99%)
    5 / 496 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 503 (0.60%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 503 (1.59%)
    6 / 496 (1.21%)
         occurrences causally related to treatment / all
    1 / 8
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    5 / 503 (0.99%)
    5 / 496 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    9 / 503 (1.79%)
    13 / 496 (2.62%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestinal obstruction
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 503 (0.99%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obturator hernia
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal tenesmus
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 503 (0.60%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 503 (0.99%)
    12 / 496 (2.42%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder dilatation
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 503 (0.40%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Renal failure chronic
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    2 / 503 (0.40%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         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
    2 / 503 (0.40%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    4 / 503 (0.80%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    4 / 503 (0.80%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 503 (0.00%)
    3 / 496 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    3 / 503 (0.60%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice extrahepatic obstructive
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 503 (0.40%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (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 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 503 (0.60%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 503 (0.00%)
    4 / 496 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (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 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 503 (0.20%)
    3 / 496 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 503 (0.00%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 503 (0.20%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 503 (0.40%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Nail infection
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 503 (1.39%)
    2 / 496 (0.40%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (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
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 503 (0.20%)
    5 / 496 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Septic shock
         subjects affected / exposed
    1 / 503 (0.20%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder abscess
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 496 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 503 (1.39%)
    9 / 496 (1.81%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 496 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cetuximab Panitumumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    475 / 503 (94.43%)
    462 / 496 (93.15%)
    Investigations
    Weight decreased
         subjects affected / exposed
    21 / 503 (4.17%)
    26 / 496 (5.24%)
         occurrences all number
    25
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    40 / 503 (7.95%)
    40 / 496 (8.06%)
         occurrences all number
    46
    49
    Dyspnoea
         subjects affected / exposed
    33 / 503 (6.56%)
    21 / 496 (4.23%)
         occurrences all number
    44
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 503 (6.16%)
    30 / 496 (6.05%)
         occurrences all number
    39
    55
    Nervous system disorders
    Headache
         subjects affected / exposed
    36 / 503 (7.16%)
    17 / 496 (3.43%)
         occurrences all number
    48
    18
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    46 / 503 (9.15%)
    32 / 496 (6.45%)
         occurrences all number
    55
    44
    Fatigue
         subjects affected / exposed
    86 / 503 (17.10%)
    72 / 496 (14.52%)
         occurrences all number
    130
    97
    Oedema peripheral
         subjects affected / exposed
    35 / 503 (6.96%)
    20 / 496 (4.03%)
         occurrences all number
    47
    22
    Pyrexia
         subjects affected / exposed
    53 / 503 (10.54%)
    28 / 496 (5.65%)
         occurrences all number
    74
    34
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    47 / 503 (9.34%)
    27 / 496 (5.44%)
         occurrences all number
    57
    31
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    74 / 503 (14.71%)
    54 / 496 (10.89%)
         occurrences all number
    103
    79
    Constipation
         subjects affected / exposed
    72 / 503 (14.31%)
    39 / 496 (7.86%)
         occurrences all number
    88
    45
    Diarrhoea
         subjects affected / exposed
    87 / 503 (17.30%)
    89 / 496 (17.94%)
         occurrences all number
    129
    158
    Dyspepsia
         subjects affected / exposed
    27 / 503 (5.37%)
    19 / 496 (3.83%)
         occurrences all number
    31
    19
    Nausea
         subjects affected / exposed
    57 / 503 (11.33%)
    66 / 496 (13.31%)
         occurrences all number
    77
    91
    Stomatitis
         subjects affected / exposed
    34 / 503 (6.76%)
    26 / 496 (5.24%)
         occurrences all number
    42
    41
    Vomiting
         subjects affected / exposed
    50 / 503 (9.94%)
    49 / 496 (9.88%)
         occurrences all number
    65
    71
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    69 / 503 (13.72%)
    52 / 496 (10.48%)
         occurrences all number
    137
    98
    Dermatitis acneiform
         subjects affected / exposed
    136 / 503 (27.04%)
    140 / 496 (28.23%)
         occurrences all number
    274
    250
    Dry skin
         subjects affected / exposed
    79 / 503 (15.71%)
    83 / 496 (16.73%)
         occurrences all number
    95
    119
    Nail disorder
         subjects affected / exposed
    31 / 503 (6.16%)
    26 / 496 (5.24%)
         occurrences all number
    50
    38
    Pruritus
         subjects affected / exposed
    89 / 503 (17.69%)
    83 / 496 (16.73%)
         occurrences all number
    124
    129
    Rash
         subjects affected / exposed
    257 / 503 (51.09%)
    249 / 496 (50.20%)
         occurrences all number
    530
    494
    Skin fissures
         subjects affected / exposed
    43 / 503 (8.55%)
    42 / 496 (8.47%)
         occurrences all number
    55
    66
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    37 / 503 (7.36%)
    35 / 496 (7.06%)
         occurrences all number
    50
    44
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    77 / 503 (15.31%)
    70 / 496 (14.11%)
         occurrences all number
    102
    84
    Hypocalcaemia
         subjects affected / exposed
    17 / 503 (3.38%)
    26 / 496 (5.24%)
         occurrences all number
    28
    43
    Hypokalaemia
         subjects affected / exposed
    23 / 503 (4.57%)
    41 / 496 (8.27%)
         occurrences all number
    44
    57
    Hypomagnesaemia
         subjects affected / exposed
    91 / 503 (18.09%)
    135 / 496 (27.22%)
         occurrences all number
    184
    310
    Infections and infestations
    Paronychia
         subjects affected / exposed
    75 / 503 (14.91%)
    58 / 496 (11.69%)
         occurrences all number
    150
    116
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 503 (5.57%)
    14 / 496 (2.82%)
         occurrences all number
    37
    15

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2012
    - clarified that crossover was not permitted on study while a subject was receiving study treatment - clarified that subjects were to be treated until disease progression, intolerability, withdrawal of consent, or death and were to be followed for survival until death, full withdrawal of consent, or end of the long term follow-up period - included definitions of primary completion (the time when the last subject was assessed or received an intervention for the purposes of final collection of data for the primary endpoint of OS) and end of study (the time when the last subject was assessed or received an intervention for evaluation in the study [eg, during follow-up]) - clarified rules for missed doses and dose withholding  clarified that Amgen could do additional testing on samples collected (blood or tumor tissue) in the study for any of the tests outlined in the protocol, for any tests necessary to minimize risks to study subjects, and for other exploratory research (if consent was provided). - clarified that sites were allowed to conduct a search of public records, such as those establishing survival status, to obtain survival data for any subject for whom survival status was not known at time of data cutoff for the primary and/or final analysis

    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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