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    Clinical Trial Results:
    Open-label, randomized, controlled, multicenter Phase II study investigating 2 cilengitide regimens in combination with cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to cetuximab and platinum-based chemotherapy alone as first-line treatment for patients with advanced Non Small Cell Lung Cancer (NSCLC).

    Summary
    EudraCT number
    2008-004148-35
    Trial protocol
    IE   BE   DE   ES   FR   IT   CZ  
    Global end of trial date
    29 Jul 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    23 May 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR200037-014
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00842712
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Str. 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre, Merck KGaA, 49 6151-72-5200, service@merckgroup.com
    Scientific contact
    Communication Centre, Merck KGaA, 49 6151-72-5200, service@merckgroup.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
    29 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of cilengitide in combination with cetuximab and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to cetuximab and platinum-based chemotherapy alone in terms of progression free survival (PFS) time (based on independent assessment, IRC) in the total population (regardless of endothelial growth factor receptor [EGFR] expression) and in the subgroup of subjects with high EGFR expression.
    Protection of trial subjects
    In this trial highest medical and ethical standards were followed, in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Belgium: 35
    Country: Number of subjects enrolled
    France: 61
    Country: Number of subjects enrolled
    Germany: 60
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Poland: 37
    Worldwide total number of subjects
    232
    EEA total number of subjects
    232
    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)
    182
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First/last subject (informed consent): Feb 2009/Jun 2012. Clinical data cut-off: 26 Jun 2013, Study completion date: July 2013.

    Pre-assignment
    Screening details
    In safety run-in part of study, a total of 12 subjects were enrolled and treated. In randomized part of study, 220 subjects were enrolled and out of these 220 subjects, 215 were treated.

    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
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy
    Arm description
    Cilengitide (Cil) was administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine (Gem) was administed at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8.

    Arm title
    Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy
    Arm description
    Cilengitide (cil) was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] at a dose of 25 mg/m^2 or Cisplatin [Cis] at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine at a dos 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle until progressive disease, death, unacceptable toxicity, or consent withdrawal.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at a dose of 80 mg/m^2 intravenous infusion on Day 1 + Vinorelbine was administered at a dose of 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Arm title
    Randomized Part: Cetuximab + Chemotherapy
    Arm description
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 was administered as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [Cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] was administered at a dose of 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine [Gem] at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal.

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine was administered at a dose of 25 mg/m^2 or Cisplatin was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Arm title
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem
    Arm description
    Cilengitide (Cil) was administered at a dose of 1000 milligram (mg) as intravenous infusion twice weekly over 1 hour on Days 1 and 4 along with Cetuximab at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1 plus Cisplatin (Cis) 75 mg/m^2 intravenous infusion on Day 1 and Gemcitabine (Gem) at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 for a period of 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin (Cis) was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (Gem) was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Arm title
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin
    Arm description
    Cilengitide was administered at a dose of 1000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin [Cis] was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered ata dose of 75 mg/m^2 as intravenous infusion on Day 1.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine was administered at a dose of 25 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks.

    Arm title
    Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem
    Arm description
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine (Gem) was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at dose of 75 mg/m^2 as intravenous infusion on Day 1.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gem was administered at a dose of 1250 mg/m^2 intravenous infusion on Days 1 and 8 for 3 weeks.

    Arm title
    Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
    Arm description
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4.

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered at a dose of 400 mg/m^2 intravenous infusion over 2 hours on Day 1.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Number of subjects in period 1
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
    Started
    85
    51
    84
    3
    3
    3
    3
    Completed
    85
    50
    78
    3
    1
    3
    2
    Not completed
    0
    1
    6
    0
    2
    0
    1
         Progressive disease
    -
    -
    -
    -
    1
    -
    1
         Randomized but not treated
    -
    1
    4
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    -
    -
         Ongoing at cut-off date
    -
    -
    2
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy
    Reporting group description
    Cilengitide (Cil) was administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine (Gem) was administed at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy
    Reporting group description
    Cilengitide (cil) was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] at a dose of 25 mg/m^2 or Cisplatin [Cis] at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine at a dos 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Randomized Part: Cetuximab + Chemotherapy
    Reporting group description
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 was administered as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [Cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] was administered at a dose of 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine [Gem] at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem
    Reporting group description
    Cilengitide (Cil) was administered at a dose of 1000 milligram (mg) as intravenous infusion twice weekly over 1 hour on Days 1 and 4 along with Cetuximab at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1 plus Cisplatin (Cis) 75 mg/m^2 intravenous infusion on Day 1 and Gemcitabine (Gem) at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 for a period of 3 weeks.

    Reporting group title
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin
    Reporting group description
    Cilengitide was administered at a dose of 1000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin [Cis] was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Reporting group title
    Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem
    Reporting group description
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine (Gem) was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Reporting group title
    Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
    Reporting group description
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Reporting group values
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin Total
    Number of subjects
    85 51 84 3 3 3 3 232
    Age categorical
    Units: Subjects
        Less than 65 years
    68 37 66 3 2 3 3 182
        Greater than or equal to 65 years
    17 14 18 0 1 0 0 50
    Gender categorical
    Units: Subjects
        Female
    34 19 27 1 0 2 2 85
        Male
    51 32 57 2 3 1 1 147

    End points

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    End points reporting groups
    Reporting group title
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy
    Reporting group description
    Cilengitide (Cil) was administered at a dose of 2000 mg as intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine (Gem) was administed at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy
    Reporting group description
    Cilengitide (cil) was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] at a dose of 25 mg/m^2 or Cisplatin [Cis] at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine at a dos 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Randomized Part: Cetuximab + Chemotherapy
    Reporting group description
    Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab at a dose of 250 mg/m^2 was administered as intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cisplatin [Cis] at a dose of 80 mg/m^2 was administered as intravenous infusion on Day 1 + Vinorelbine [Vin] was administered at a dose of 25 mg/m^2 or Cisplatin at a dose of 75 mg/m^2 was administered as intravenous infusion on Day 1 + Gemcitabine [Gem] at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 of each 3-week cycle) along with Cilengitide and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem
    Reporting group description
    Cilengitide (Cil) was administered at a dose of 1000 milligram (mg) as intravenous infusion twice weekly over 1 hour on Days 1 and 4 along with Cetuximab at a dose of 400 milligram per square meter (mg/m^2) as intravenous infusion over 2 hours on Day 1 plus Cisplatin (Cis) 75 mg/m^2 intravenous infusion on Day 1 and Gemcitabine (Gem) at a dose of 1250 mg/m^2 was administered as intravenous infusion on Days 1 and 8 for a period of 3 weeks.

    Reporting group title
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin
    Reporting group description
    Cilengitide was administered at a dose of 1000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin [Cis] was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Reporting group title
    Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem
    Reporting group description
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 75 mg/m^2 as intravenous infusion on Day 1 + Gemcitabine (Gem) was administered at a dose of 1250 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Reporting group title
    Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
    Reporting group description
    Cilengitide was administered at a dose of 2000 mg as intravenous infusion twice weekly over 1 hour on Days 1 and 4 + Cetuximab was administered at a dose of 400 mg/m^2 as intravenous infusion over 2 hours on Day 1 + Cisplatin (Cis) was administered at a dose of 80 mg/m^2 as intravenous infusion on Day 1 + Vinorelbine (Vin) was administered at a dose of 25 mg/m^2 as intravenous infusion on Days 1 and 8 for 3 weeks.

    Primary: Safety run-in Part: Number of subjects with dose limiting toxicities (DLTs)

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    End point title
    Safety run-in Part: Number of subjects with dose limiting toxicities (DLTs) [1] [2]
    End point description
    The DLT population included all subjects who completed first 3 weeks of treatment (first chemotherapy cycle) or who discontinued treatment due to any DLT during the first 3 weeks of treatment in the safetyrun-in part.
    End point type
    Primary
    End point timeframe
    Up to Week 3
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analyses was not planned for this outcome measure.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistics was reported only for the groups in the safety run-in part of the study as per planned analysis
    End point values
    Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Gem Safety run-in Part: Cil (1000 mg) + Cetuximab + Cis + Vin Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Gem Safety run-in Part: Cil (2000 mg) + Cetuximab + Cis + Vin
    Number of subjects analysed
    3
    3
    3
    3
    Units: Subjects
        Independent Read
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Randomized part: Progression free survival (PFS) time - Independent read

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    End point title
    Randomized part: Progression free survival (PFS) time - Independent read [3]
    End point description
    The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Independent Read is the assessment of all imaging centrally by an Independent Review Committee (IRC). Intent-to-treat (ITT) population included all participants who were randomized to trial treatment.
    End point type
    Primary
    End point timeframe
    Time from randomization until disease progression, death or last tumor assessment, reported between day of first subject randomized, that is, Feb 2009 until cut-off date, (26 Jun 2013).
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistics was reported only for the groups in the randomized part of the study as per planned analysis
    End point values
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy
    Number of subjects analysed
    85
    51
    84
    Units: Months
        median (confidence interval 95%)
    6.2 (5.6 to 7.4)
    5.6 (4 to 7.5)
    5 (4.2 to 5.6)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy v Randomized Part: Cetuximab + Chemotherapy
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0845
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.718
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.492
         upper limit
    1.048

    Secondary: Randomized Part: Progression Free Survival (PFS) Time - Investigator Read

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    End point title
    Randomized Part: Progression Free Survival (PFS) Time - Investigator Read [4]
    End point description
    The PFS time is defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read is the assessment of all imaging by the treating physician at the local trial site. ITT population included all participants who were randomized to trial treatment.
    End point type
    Secondary
    End point timeframe
    Time from randomization until disease progression, death or last tumor assessment, reported between day of first subject randomized, that is, Feb 2009 until cut-off date, (26 Jun 2013).
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistics was reported only for the groups in the randomized part of the study as per planned analysis
    End point values
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy
    Number of subjects analysed
    85
    51
    84
    Units: Months
        median (confidence interval 95%)
    5.6 (5.4 to 6.7)
    5.6 (4.2 to 7)
    5.3 (4.2 to 5.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy v Randomized Part: Cetuximab + Chemotherapy
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5912
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.909
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.642
         upper limit
    1.286

    Secondary: Randomized Part: Overall Survival (OS) Time

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    End point title
    Randomized Part: Overall Survival (OS) Time [5]
    End point description
    The OS time is defined as the time (in months) from randomization to death or last day known to be alive. Subjects without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. ITT population included all participants who were randomized to trial treatment.
    End point type
    Secondary
    End point timeframe
    Time from randomization until death or last day known to be alive, reported between day of first subject randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013).
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistics was reported only for the groups in the randomized part of the study as per planned analysis
    End point values
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy
    Number of subjects analysed
    85
    51
    84
    Units: months
        median (confidence interval 95%)
    13.6 (9.5 to 18.6)
    13.6 (8.7 to 16.7)
    9.7 (7.9 to 13.4)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy v Randomized Part: Cetuximab + Chemotherapy
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2648
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.813
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.564
         upper limit
    1.171

    Secondary: Randomized Part: Best Overall Response (BOR) Rate

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    End point title
    Randomized Part: Best Overall Response (BOR) Rate [6]
    End point description
    The BOR rate is defined as the percentage of subjects having achieved confirmed complete response (CR) or partial response (PR) as the best overall response, based on radiological assessments (based on response evaluation criteria in solid tumors [RECIST]) as assessed by Independent Review Committee (IRC): CR = disappearance of all target lesions; PR = at least 30% decrease in the sum of the longest diameter of target lesions. ITT population included all participants who were randomized to trial treatment.
    End point type
    Secondary
    End point timeframe
    Time from randomization until treatment failure or last tumor assessment, reported between day of first subject randomized, that was, Feb 2009 until cut-off date,(26 Jun 2013)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistics was reported only for the groups in the randomized part of the study as per planned analysis
    End point values
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy
    Number of subjects analysed
    85
    51
    84
    Units: percentage
        number (confidence interval 95%)
    37.6 (27.4 to 48.8)
    27.5 (15.9 to 41.7)
    29.8 (20.3 to 40.7)
    No statistical analyses for this end point

    Secondary: Randomized Part: Time to Treatment Failure

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    End point title
    Randomized Part: Time to Treatment Failure [7]
    End point description
    Time to treatment failure was defined as the time from first administration of trial treatment until the date of the first occurrence of one of the events defining treatment failure: Progressive Disease (PD) assessed by the investigator, discontinuation of treatment due to PD, discontinuation of treatment due to an adverse event (AE), start of any new anticancer therapy, or withdrawal of consent or death within 60 days of the last tumor assessment or first administration of trial treatment. Time to treatment failure was assessed according to modified World Health Organization (WHO) criteria by Independent Review Committee (IRC). ITT population included all participants who were randomized to trial treatment.
    End point type
    Secondary
    End point timeframe
    Time from randomization until treatment failure or last tumor assessment, reported between day of first subject randomized, that is, Feb 2009 until cut-off date,(26 Jun 2013).
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistics was reported only for the groups in the randomized part of the study as per planned analysis
    End point values
    Randomized Part: Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Randomized Part: Cetuximab + Chemotherapy
    Number of subjects analysed
    85
    51
    84
    Units: months
        median (confidence interval 95%)
    4.4 (3.5 to 5.6)
    2.8 (1.4 to 4.2)
    4.2 (2.8 to 5.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time from first dose up to 28 days after last dose of study treatment, reported between day of first subject randomized, that was, Feb 2009 until cut-off date (26 Jun 2013)
    Adverse event reporting additional description
    The analysis was performed on safety population, defined as all subjects who received any dose of the trial treatment (cilengitide, cetuximab, or chemotherapy), whereby subjects were analyzed according to the actual treatment they received.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Cil (Once Weekly) + Cetuximab + Chemotherapy
    Reporting group description
    Cil 2000 mg intravenous infusion once weekly over 1 hour on Days 1, 8 and 15 of each 3-week cycle + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 or Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy
    Reporting group description
    Cil 2000 mg intravenous infusion twice weekly over 1 hour on Days 1, 4, 8, 11, 15, and 18 of each 3-week cycle followed by once weekly administration after end of chemotherapy + Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 or Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Reporting group title
    Cetuximab + Chemotherapy
    Reporting group description
    Cetuximab 400 mg/m^2 intravenous infusion over 2 hours on Day 1 of Cycle 1 followed by cetuximab 250 mg/m^2 intravenous infusion over 1 hour once weekly on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of all subsequent cycles until progressive disease, death, unacceptable toxicity, or consent withdrawal. Chemotherapy (Cis 80 mg/m^2 intravenous infusion on Day 1 + Vin 25 mg/m^2 or Cis 75 mg/m^2 intravenous infusion on Day 1 + Gem 1250 mg/m^2 intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered along with Cil and cetuximab as per Investigator's discretion up to a maximum of 6 cycles.

    Serious adverse events
    Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Cetuximab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 85 (49.41%)
    29 / 50 (58.00%)
    45 / 80 (56.25%)
         number of deaths (all causes)
    56
    39
    58
         number of deaths resulting from adverse events
    Vascular disorders
    AORTIC THROMBOSIS
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTERIAL DISORDER
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTERIAL THROMBOSIS LIMB
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AXILLARY VEIN THROMBOSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOVOLAEMIC SHOCK
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    JUGULAR VEIN THROMBOSIS
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL EMBOLISM
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SHOCK
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    SUBCLAVIAN VEIN THROMBOSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUPERIOR VENA CAVA SYNDROME
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENA CAVA THROMBOSIS
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MALIGNANT PLEURAL EFFUSION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO MENINGES
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    TUMOUR EMBOLISM
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DISEASE PROGRESSION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    FATIGUE
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    4 / 85 (4.71%)
    1 / 50 (2.00%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    IMPAIRED HEALING
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MEDICAL DEVICE COMPLICATION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FAILURE TO ANASTOMOSE
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INCISIONAL HERNIA
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIMB INJURY
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPLENIC RUPTURE
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARRHYTHMIA SUPRAVENTRICULAR
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STRESS CARDIOMYOPATHY
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    4 / 85 (4.71%)
    5 / 50 (10.00%)
    8 / 80 (10.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 5
    1 / 8
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    PULMONARY THROMBOSIS
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 50 (4.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE BONE MARROW APLASIA
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    4 / 85 (4.71%)
    1 / 50 (2.00%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CENTRAL NERVOUS SYSTEM LESION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 50 (4.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COMA
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CONVULSION
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STATUS EPILEPTICUS
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    PERIORBITAL OEDEMA
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    HYPOACUSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULAR PERFORATION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER HAEMORRHAGE
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 50 (4.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROCTITIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 50 (2.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    NAIL BED INFECTION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROTEUS INFECTION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 50 (4.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SKIN INFECTION
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 50 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cil (Once Weekly) + Cetuximab + Chemotherapy Randomized Part: Cil (Twice Weekly) + Cetuximab + Chemotherapy Cetuximab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    84 / 85 (98.82%)
    48 / 50 (96.00%)
    78 / 80 (97.50%)
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 50 (2.00%)
    0 / 80 (0.00%)
         occurrences all number
    5
    1
    0
    HYPERTENSION
         subjects affected / exposed
    9 / 85 (10.59%)
    6 / 50 (12.00%)
    5 / 80 (6.25%)
         occurrences all number
    9
    6
    5
    HYPOTENSION
         subjects affected / exposed
    1 / 85 (1.18%)
    4 / 50 (8.00%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    4
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    20 / 85 (23.53%)
    15 / 50 (30.00%)
    23 / 80 (28.75%)
         occurrences all number
    20
    15
    23
    CHEST PAIN
         subjects affected / exposed
    5 / 85 (5.88%)
    5 / 50 (10.00%)
    2 / 80 (2.50%)
         occurrences all number
    5
    5
    2
    CHILLS
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 50 (6.00%)
    2 / 80 (2.50%)
         occurrences all number
    2
    3
    2
    FATIGUE
         subjects affected / exposed
    29 / 85 (34.12%)
    13 / 50 (26.00%)
    19 / 80 (23.75%)
         occurrences all number
    29
    13
    19
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 50 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    2
    0
    4
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 50 (4.00%)
    2 / 80 (2.50%)
         occurrences all number
    5
    2
    2
    OEDEMA PERIPHERAL
         subjects affected / exposed
    5 / 85 (5.88%)
    5 / 50 (10.00%)
    5 / 80 (6.25%)
         occurrences all number
    5
    5
    5
    PYREXIA
         subjects affected / exposed
    8 / 85 (9.41%)
    14 / 50 (28.00%)
    15 / 80 (18.75%)
         occurrences all number
    8
    14
    15
    XEROSIS
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    1
    4
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    4 / 85 (4.71%)
    4 / 50 (8.00%)
    9 / 80 (11.25%)
         occurrences all number
    4
    4
    9
    DEPRESSION
         subjects affected / exposed
    3 / 85 (3.53%)
    2 / 50 (4.00%)
    4 / 80 (5.00%)
         occurrences all number
    3
    2
    4
    INSOMNIA
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 50 (6.00%)
    9 / 80 (11.25%)
         occurrences all number
    4
    3
    9
    HAEMATURIA
         subjects affected / exposed
    0 / 85 (0.00%)
    3 / 50 (6.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    3
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 50 (2.00%)
    1 / 80 (1.25%)
         occurrences all number
    6
    1
    1
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    3 / 85 (3.53%)
    5 / 50 (10.00%)
    5 / 80 (6.25%)
         occurrences all number
    3
    5
    5
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 85 (5.88%)
    0 / 50 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    5
    0
    4
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    8 / 85 (9.41%)
    7 / 50 (14.00%)
    8 / 80 (10.00%)
         occurrences all number
    8
    7
    8
    PLATELET COUNT DECREASED
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 50 (2.00%)
    3 / 80 (3.75%)
         occurrences all number
    5
    1
    3
    WEIGHT DECREASED
         subjects affected / exposed
    9 / 85 (10.59%)
    3 / 50 (6.00%)
    15 / 80 (18.75%)
         occurrences all number
    9
    3
    15
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 50 (2.00%)
    3 / 80 (3.75%)
         occurrences all number
    6
    1
    3
    Cardiac disorders
    TACHYCARDIA
         subjects affected / exposed
    1 / 85 (1.18%)
    3 / 50 (6.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    3
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    13 / 85 (15.29%)
    11 / 50 (22.00%)
    12 / 80 (15.00%)
         occurrences all number
    13
    11
    12
    DYSPHONIA
         subjects affected / exposed
    2 / 85 (2.35%)
    2 / 50 (4.00%)
    5 / 80 (6.25%)
         occurrences all number
    2
    2
    5
    DYSPNOEA
         subjects affected / exposed
    11 / 85 (12.94%)
    6 / 50 (12.00%)
    5 / 80 (6.25%)
         occurrences all number
    11
    6
    5
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    9 / 85 (10.59%)
    10 / 50 (20.00%)
    7 / 80 (8.75%)
         occurrences all number
    9
    10
    7
    EPISTAXIS
         subjects affected / exposed
    10 / 85 (11.76%)
    10 / 50 (20.00%)
    13 / 80 (16.25%)
         occurrences all number
    10
    10
    13
    HAEMOPTYSIS
         subjects affected / exposed
    3 / 85 (3.53%)
    4 / 50 (8.00%)
    7 / 80 (8.75%)
         occurrences all number
    3
    4
    7
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 50 (2.00%)
    5 / 80 (6.25%)
         occurrences all number
    0
    1
    5
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    33 / 85 (38.82%)
    22 / 50 (44.00%)
    24 / 80 (30.00%)
         occurrences all number
    33
    22
    24
    LEUKOPENIA
         subjects affected / exposed
    20 / 85 (23.53%)
    7 / 50 (14.00%)
    10 / 80 (12.50%)
         occurrences all number
    20
    7
    10
    LYMPHOPENIA
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 50 (6.00%)
    4 / 80 (5.00%)
         occurrences all number
    4
    3
    4
    NEUTROPENIA
         subjects affected / exposed
    43 / 85 (50.59%)
    22 / 50 (44.00%)
    35 / 80 (43.75%)
         occurrences all number
    46
    22
    35
    THROMBOCYTOPENIA
         subjects affected / exposed
    29 / 85 (34.12%)
    17 / 50 (34.00%)
    24 / 80 (30.00%)
         occurrences all number
    29
    17
    24
    THROMBOCYTOSIS
         subjects affected / exposed
    3 / 85 (3.53%)
    4 / 50 (8.00%)
    1 / 80 (1.25%)
         occurrences all number
    3
    4
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    8 / 85 (9.41%)
    4 / 50 (8.00%)
    2 / 80 (2.50%)
         occurrences all number
    8
    4
    2
    DYSGEUSIA
         subjects affected / exposed
    7 / 85 (8.24%)
    4 / 50 (8.00%)
    5 / 80 (6.25%)
         occurrences all number
    7
    4
    5
    HEADACHE
         subjects affected / exposed
    9 / 85 (10.59%)
    6 / 50 (12.00%)
    6 / 80 (7.50%)
         occurrences all number
    9
    6
    6
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    1 / 85 (1.18%)
    3 / 50 (6.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    3
    1
    PARAESTHESIA
         subjects affected / exposed
    3 / 85 (3.53%)
    1 / 50 (2.00%)
    8 / 80 (10.00%)
         occurrences all number
    3
    1
    8
    Eye disorders
    CONJUNCTIVITIS
         subjects affected / exposed
    10 / 85 (11.76%)
    7 / 50 (14.00%)
    5 / 80 (6.25%)
         occurrences all number
    10
    7
    5
    Ear and labyrinth disorders
    TINNITUS
         subjects affected / exposed
    1 / 85 (1.18%)
    3 / 50 (6.00%)
    6 / 80 (7.50%)
         occurrences all number
    1
    3
    6
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    7 / 85 (8.24%)
    2 / 50 (4.00%)
    6 / 80 (7.50%)
         occurrences all number
    7
    2
    6
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    7 / 85 (8.24%)
    5 / 50 (10.00%)
    6 / 80 (7.50%)
         occurrences all number
    7
    5
    6
    CONSTIPATION
         subjects affected / exposed
    17 / 85 (20.00%)
    14 / 50 (28.00%)
    19 / 80 (23.75%)
         occurrences all number
    17
    14
    19
    DIARRHOEA
         subjects affected / exposed
    22 / 85 (25.88%)
    14 / 50 (28.00%)
    22 / 80 (27.50%)
         occurrences all number
    22
    14
    19
    DYSPEPSIA
         subjects affected / exposed
    4 / 85 (4.71%)
    5 / 50 (10.00%)
    2 / 80 (2.50%)
         occurrences all number
    4
    5
    2
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 85 (0.00%)
    3 / 50 (6.00%)
    1 / 80 (1.25%)
         occurrences all number
    0
    3
    1
    HAEMORRHOIDS
         subjects affected / exposed
    2 / 85 (2.35%)
    4 / 50 (8.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    4
    1
    NAUSEA
         subjects affected / exposed
    50 / 85 (58.82%)
    27 / 50 (54.00%)
    42 / 80 (52.50%)
         occurrences all number
    50
    27
    42
    STOMATITIS
         subjects affected / exposed
    15 / 85 (17.65%)
    10 / 50 (20.00%)
    11 / 80 (13.75%)
         occurrences all number
    15
    10
    11
    VOMITING
         subjects affected / exposed
    18 / 85 (21.18%)
    14 / 50 (28.00%)
    23 / 80 (28.75%)
         occurrences all number
    18
    14
    23
    Renal and urinary disorders
    DYSURIA
         subjects affected / exposed
    4 / 85 (4.71%)
    4 / 50 (8.00%)
    1 / 80 (1.25%)
         occurrences all number
    4
    4
    1
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    19 / 85 (22.35%)
    11 / 50 (22.00%)
    17 / 80 (21.25%)
         occurrences all number
    19
    11
    17
    ALOPECIA
         subjects affected / exposed
    13 / 85 (15.29%)
    7 / 50 (14.00%)
    9 / 80 (11.25%)
         occurrences all number
    13
    7
    9
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    17 / 85 (20.00%)
    7 / 50 (14.00%)
    16 / 80 (20.00%)
         occurrences all number
    17
    7
    16
    DRY SKIN
         subjects affected / exposed
    13 / 85 (15.29%)
    5 / 50 (10.00%)
    9 / 80 (11.25%)
         occurrences all number
    13
    5
    9
    ERYTHEMA
         subjects affected / exposed
    1 / 85 (1.18%)
    5 / 50 (10.00%)
    4 / 80 (5.00%)
         occurrences all number
    1
    5
    4
    NAIL TOXICITY
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 50 (6.00%)
    1 / 80 (1.25%)
         occurrences all number
    4
    3
    1
    PRURITUS
         subjects affected / exposed
    7 / 85 (8.24%)
    6 / 50 (12.00%)
    3 / 80 (3.75%)
         occurrences all number
    7
    6
    3
    RASH
         subjects affected / exposed
    35 / 85 (41.18%)
    17 / 50 (34.00%)
    29 / 80 (36.25%)
         occurrences all number
    35
    17
    29
    SKIN FISSURES
         subjects affected / exposed
    6 / 85 (7.06%)
    2 / 50 (4.00%)
    6 / 80 (7.50%)
         occurrences all number
    6
    2
    6
    SKIN TOXICITY
         subjects affected / exposed
    10 / 85 (11.76%)
    8 / 50 (16.00%)
    7 / 80 (8.75%)
         occurrences all number
    10
    8
    7
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 50 (2.00%)
    5 / 80 (6.25%)
         occurrences all number
    2
    1
    5
    BACK PAIN
         subjects affected / exposed
    13 / 85 (15.29%)
    8 / 50 (16.00%)
    8 / 80 (10.00%)
         occurrences all number
    13
    8
    8
    MUSCLE SPASMS
         subjects affected / exposed
    2 / 85 (2.35%)
    4 / 50 (8.00%)
    2 / 80 (2.50%)
         occurrences all number
    2
    4
    2
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 50 (2.00%)
    4 / 80 (5.00%)
         occurrences all number
    2
    1
    4
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 50 (6.00%)
    4 / 80 (5.00%)
         occurrences all number
    4
    3
    4
    PAIN IN EXTREMITY
         subjects affected / exposed
    10 / 85 (11.76%)
    3 / 50 (6.00%)
    6 / 80 (7.50%)
         occurrences all number
    10
    3
    6
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    30 / 85 (35.29%)
    13 / 50 (26.00%)
    21 / 80 (26.25%)
         occurrences all number
    30
    13
    21
    HYPERKALAEMIA
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 50 (6.00%)
    3 / 80 (3.75%)
         occurrences all number
    2
    3
    3
    HYPOCALCAEMIA
         subjects affected / exposed
    6 / 85 (7.06%)
    3 / 50 (6.00%)
    6 / 80 (7.50%)
         occurrences all number
    6
    3
    6
    HYPOKALAEMIA
         subjects affected / exposed
    11 / 85 (12.94%)
    5 / 50 (10.00%)
    7 / 80 (8.75%)
         occurrences all number
    11
    5
    7
    HYPOMAGNESAEMIA
         subjects affected / exposed
    18 / 85 (21.18%)
    10 / 50 (20.00%)
    7 / 80 (8.75%)
         occurrences all number
    18
    10
    7
    HYPONATRAEMIA
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 50 (2.00%)
    2 / 80 (2.50%)
         occurrences all number
    6
    1
    2
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    3 / 85 (3.53%)
    3 / 50 (6.00%)
    5 / 80 (6.25%)
         occurrences all number
    3
    3
    5
    FOLLICULITIS
         subjects affected / exposed
    2 / 85 (2.35%)
    5 / 50 (10.00%)
    5 / 80 (6.25%)
         occurrences all number
    2
    5
    5
    NASOPHARYNGITIS
         subjects affected / exposed
    5 / 85 (5.88%)
    5 / 50 (10.00%)
    7 / 80 (8.75%)
         occurrences all number
    5
    5
    7
    PARONYCHIA
         subjects affected / exposed
    14 / 85 (16.47%)
    1 / 50 (2.00%)
    8 / 80 (10.00%)
         occurrences all number
    14
    1
    8
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 50 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    0
    14

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Dec 2008
    To be compliant with the suggestions of health authorities: Additional exclusion criteria due to contra-indications and precautions included in the approved summary of product characteristics of vinorelbine, gemcitabine, and cisplatin were included, the safety monitoring of hematological and biochemistry parameters during the safety run-in part of the protocol were intensified to rule out the synergistic toxicities. The sequence of administration of the platinum-based chemotherapy (cisplatin, vinorelbine, and gemcitabine) was corrected to comply with the summary of product characteristics information.
    25 Nov 2009
    As per this amendment, the final dose of cilengitide for the randomized part of the study will be increased to 2000 mg/m^2 after the safety run-in part has been completed. The dose of gemcitabine will be increased from 1000 mg/m^2 on day 1 and 8 to the standard label dose of 1250 mg/m^2 gemcitabine on day 1 and 8, additional cardiac safety monitoring would be implemented, changes in the exclusion criteria with respect to partial thromboplastin time, addition of exclusion criteria pertaining to concurrent chronic immunosuppressive or hormone anti-cancer therapy, decreasing timepoints for the collection of circulating endothelial cells or circulating tumor cells, to update safety information of cetuximab and cilengitide.
    20 Dec 2010
    The purpose of this amendment was to adjust the sample size and number of study centers, to stop randomizing subjects to Group B on cilengitide 2000 mg twice weekly in combination with cetuximab and platinum-based chemotherapy, a pre-screening visit was added for the assessment of EGFR expression by immunohistochemistry and selective recruitment of subjects with high epidermal growth factor receptor.

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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