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    Clinical Trial Results:
    Cilengitide for subjects with newly diagnosed glioblastoma multiforme and methylated MGMT gene promoter - a multicenter, open-label, controlled Phase III study, testing cilengitide in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy) versus standard treatment alone (CENTRIC)

    Summary
    EudraCT number
    2007-004344-78
    Trial protocol
    BE   GB   AT   DE   CZ   FR   ES   IT   SK   HU   NL  
    Global end of trial date
    30 Jul 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    30 Jun 2016
    First version publication date
    26 Jul 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    EMD 121974-011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00689221
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Str. 250, Darmstadt, Germany,
    Public contact
    Communication Center, Merck KGaA, 49 6151-72-5200 , service@merckgroup.com
    Scientific contact
    Communication Center, 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
    19 Nov 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess whether overall survival time in subjects receiving cilengitide (2000 mg twice weekly intravenously in combination with standard treatment is statistically significantly prolonged compared to subjects receiving standard treatment alone.
    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
    25 Sep 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Switzerland: 16
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 54
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 117
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    India: 24
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Poland: 46
    Country: Number of subjects enrolled
    Serbia: 31
    Country: Number of subjects enrolled
    Singapore: 5
    Worldwide total number of subjects
    545
    EEA total number of subjects
    311
    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)
    420
    From 65 to 84 years
    125
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First/last subject (informed consent): Sep 2008/Aug 2011. Clinical data cut-off: 19 Nov 2012, Study completion date: Aug 2013.

    Pre-assignment
    Screening details
    Enrolled: 3471 screened for eligibility; 2926 excluded (mainly due to unmethylated O6-methylguanine-DNA methyltransferase status and non-fulfillment of inclusion or exclusion criteria), 545 subjects randomized.

    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
    Cilengitide + Temozolomide + Radiotherapy
    Arm description
    Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77, Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and radiotherapy (RTX) at a dose of 2 Gray (Gy) per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 was optional in subjects without disease progression, If considered beneficial in the opinion of the Investigator.
    Arm type
    Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Temozolomide (TMZ) 75 mg/m^2 intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34

    Investigational medicinal product name
    Cilengitide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77

    Arm title
    Temozolomide + Radiotherapy
    Arm description
    TMZ 75 mg/m^2 administered intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and RTX at a dose of 2 Gy per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason.
    Arm type
    Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34

    Number of subjects in period 1
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Started
    272
    273
    Completed
    233
    237
    Not completed
    39
    36
         Ongoing at cut-off date
    39
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cilengitide + Temozolomide + Radiotherapy
    Reporting group description
    Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77, Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and radiotherapy (RTX) at a dose of 2 Gray (Gy) per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 was optional in subjects without disease progression, If considered beneficial in the opinion of the Investigator.

    Reporting group title
    Temozolomide + Radiotherapy
    Reporting group description
    TMZ 75 mg/m^2 administered intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and RTX at a dose of 2 Gy per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason.

    Reporting group values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy Total
    Number of subjects
    272 273 545
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.8 ( 11 ) 56 ( 10.97 ) -
    Gender categorical
    Units: Subjects
        Female
    124 130 254
        Male
    148 143 291

    End points

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    End points reporting groups
    Reporting group title
    Cilengitide + Temozolomide + Radiotherapy
    Reporting group description
    Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77, Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and radiotherapy (RTX) at a dose of 2 Gray (Gy) per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 was optional in subjects without disease progression, If considered beneficial in the opinion of the Investigator.

    Reporting group title
    Temozolomide + Radiotherapy
    Reporting group description
    TMZ 75 mg/m^2 administered intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and RTX at a dose of 2 Gy per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason.

    Primary: Overall survival (OS) time

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    End point title
    Overall survival (OS) time
    End point description
    The OS time was defined as the time (in months) from randomization to death or last day known to be alive. Subjects without event were censored at the last date known to be alive or at the clinical cut-off date, whatever was earlier. ITT population included all the participants who were randomized to study treatment.
    End point type
    Primary
    End point timeframe
    Time from randomization to death or last day known to be alive, reported between day of first subject randomized, that was, Sep 2008 until cut-off date, (19 Nov 2012)
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    272
    273
    Units: Months
        median (confidence interval 95%)
    26.3 (23.8 to 28.8)
    26.3 (23.9 to 34.7)
    Statistical analysis title
    Statistical Analysis 1 for Overall Survival (OS)
    Comparison groups
    Cilengitide + Temozolomide + Radiotherapy v Temozolomide + Radiotherapy
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8623
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.808
         upper limit
    1.291

    Secondary: Progression free survival (PFS) time - investigator and independent read

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    End point title
    Progression free survival (PFS) time - investigator and independent read
    End point description
    The PFS time was defined as the duration from randomization to either first observation of progressive disease (PD) or occurrence of death due to any cause. Investigator read was the assessment of all imaging by the treating physician at the local trial site. Independent Read was the assessment of all imaging centrally by an Independent Review Committee (IRC). ITT population included all the participants who were randomized to study treatment.
    End point type
    Secondary
    End point timeframe
    Time from randomization to disease progression, death or last tumor assessment, reported between day of first subject randomized, that was, Sep 2008 until cut-off date, (19 Nov 2012)
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    272
    273
    Units: Months
    median (confidence interval 95%)
        PFS Time-Investigator read
    13.5 (10.8 to 15.9)
    10.7 (8.1 to 13.3)
        PFS Time-Independent read
    10.6 (8.2 to 13.4)
    7.9 (5.9 to 12.5)
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentration (Cmax)

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    End point title
    Maximum observed plasma concentration (Cmax) [1]
    End point description
    The Cmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1. This endpoint was assessed in all subjects of "Cilengitide + Temozolomide + Radiotherapy" group who received at least 1 cilengitide dose with plasma concentration data available on Day 1 of Week -1.
    End point type
    Secondary
    End point timeframe
    Day 1 of Week -1
    Notes
    [1] - 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: Only "Cilengitide + Temozolomide + Radiotherapy" group was analyzed for this outcome measure as per planned analysis
    End point values
    Cilengitide + Temozolomide + Radiotherapy
    Number of subjects analysed
    38 [2]
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    167363 ( 368301.1 )
    Notes
    [2] - N' (number of participants analyzed) signifies those participants who were evaluable for this OM
    No statistical analyses for this end point

    Secondary: Time to maximum plasma concentration (Tmax)

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    End point title
    Time to maximum plasma concentration (Tmax) [3]
    End point description
    The Tmax for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1. This endpoint was assessed in all subjects of "Cilengitide + Temozolomide + Radiotherapy" group who received at least 1 cilengitide dose with plasma concentration data available on Day 1 of Week -1.
    End point type
    Secondary
    End point timeframe
    Day 1 of Week -1
    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: Only "Cilengitide + Temozolomide + Radiotherapy" group was analyzed for this outcome measure as per planned analysis
    End point values
    Cilengitide + Temozolomide + Radiotherapy
    Number of subjects analysed
    38 [4]
    Units: hour
        arithmetic mean (standard deviation)
    1.029 ( 0.401 )
    Notes
    [4] - N' (number of participants analyzed) signifies those participants who were evaluable for this OM
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration curve from time 0 to 6 hours (AUC [0-6]) after dose

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    End point title
    Area under the plasma concentration curve from time 0 to 6 hours (AUC [0-6]) after dose [5]
    End point description
    The AUC (0-6) for cilengitide was calculated by non-compartmental analysis using the computer program WinNonlin, Version 6.2.1. This endpoint was assessed in all subjects of "Cilengitide + Temozolomide + Radiotherapy" group who received at least 1 cilengitide dose with plasma concentration data available on Day 1 of Week -1.
    End point type
    Secondary
    End point timeframe
    Day 1 of Week -1
    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: Only "Cilengitide + Temozolomide + Radiotherapy" group was analyzed for this outcome measure as per planned analysis
    End point values
    Cilengitide + Temozolomide + Radiotherapy
    Number of subjects analysed
    37 [6]
    Units: hour*ng/mL
        arithmetic mean (standard deviation)
    295171.2 ( 198050.6 )
    Notes
    [6] - N' (number of participants analyzed) signifies those participants who were evaluable for this OM
    No statistical analyses for this end point

    Secondary: European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) sub-scale scores

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    End point title
    European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) sub-scale scores
    End point description
    The EORTC QLQ-C30 is a questionnaire including following sub-scales: global health status, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). Scores are averaged for each scale and transformed to 0-100 scale; higher score indicates better quality of life on global health status and functional scales and worse quality of life on symptom scales and financial difficulty scale. This endpoint was assessed in all subjects who were randomized to study treatment and who were evaluable for this outcome measure. 'n' signifies those subjects who were evaluable for the specified category.
    End point type
    Secondary
    End point timeframe
    Up to 50 months
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    71
    93
    Units: units on a scale
    arithmetic mean (standard deviation)
        Global Health Status (n=71, 92)
    54.34 ( 25.58 )
    55.43 ( 27.02 )
        Physical Functioning (n=71, 92)
    65.7 ( 33.01 )
    67.46 ( 31.19 )
        Role Functioning (n=71, 92)
    56.34 ( 37.31 )
    56.34 ( 35.19 )
        Emotional Functioning (n=71, 93)
    67.49 ( 30.58 )
    67 ( 27.29 )
        Cognitive Functioning (n=70, 93)
    64.05 ( 29.16 )
    65.41 ( 31.4 )
        Social Activity (n=71, 93)
    56.34 ( 36.77 )
    62.72 ( 35.73 )
        Fatigue (n=71, 92)
    44.37 ( 33.07 )
    39.73 ( 29.93 )
        Nausea and Vomiting (n=71, 93)
    10.33 ( 20.77 )
    7.71 ( 16.03 )
        Pain (n=71, 93)
    22.3 ( 29.4 )
    24.37 ( 28.93 )
        Dyspnoea (n=71, 92)
    15.96 ( 28.09 )
    13.04 ( 22.62 )
        Insomnia (n=71, 91)
    20.66 ( 30.01 )
    20.51 ( 26.65 )
        Appetite Loss (n=71, 92)
    21.13 ( 30.47 )
    15.94 ( 28.59 )
        Constipation (n=71, 93)
    18.78 ( 28.02 )
    13.98 ( 25.69 )
        Diarrhoea (n=70, 92)
    6.67 ( 18.48 )
    4.35 ( 13.28 )
        Financial difficulties (n=71, 93)
    27.23 ( 31.53 )
    22.94 ( 31.46 )
    No statistical analyses for this end point

    Secondary: European organization for the research and treatment of cancer quality of life questionnaire brain module (EORTC QLQ-BN20) sub-scale scores

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    End point title
    European organization for the research and treatment of cancer quality of life questionnaire brain module (EORTC QLQ-BN20) sub-scale scores
    End point description
    The QLQ-BN20 is a questionnaire specifically designed as the QLQ-C30 supplement for the evaluation of quality of life in brain tumor subjects. It includes 4 multi-item sub-scales: future uncertainty, visual disorder, motor dysfunction, communication deficits, and 7 single-item scales: headaches, seizures, drowsiness, itchy skin, hair loss, weakness of legs, and bladder control. All items are rated on a 4-point Likert-type scale (‘1=not at all’, ‘2=a little’, ‘3=quite a bit’ and ‘4=very much’), and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms. This endpoint was assessed in all the subjects who were randomized and who were evaluable for this outcome measure. 'n' signifies those subjects who were evaluable for the specified category.
    End point type
    Secondary
    End point timeframe
    Up to 50 months
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    68
    87
    Units: units on a scale
    arithmetic mean (standard deviation)
        Future Uncertainty (n=68, 86)
    44.49 ( 29.7 )
    39.31 ( 30.24 )
        Visual Disorder (n=68, 85)
    12.99 ( 20.24 )
    17.78 ( 23.77 )
        Motor Dysfunction (n=68, 86)
    27.45 ( 30.62 )
    23.39 ( 25.95 )
        Communication Deficit (n=68, 86)
    26.14 ( 28.59 )
    19.96 ( 27.89 )
        Headaches (n=68, 86)
    25.98 ( 32.5 )
    21.71 ( 26.45 )
        Seizures (n=68, 87)
    9.31 ( 22.93 )
    8.05 ( 20.94 )
        Drowsiness (n=66, 87)
    38.38 ( 33.71 )
    35.25 ( 31.07 )
        Itchy Skin (n=68, 86)
    9.8 ( 20 )
    13.57 ( 24.72 )
        Hair Loss (n=66, 86)
    13.13 ( 22.55 )
    15.12 ( 26.4 )
        Weakness of Legs (n=67, 85)
    24.38 ( 34.12 )
    20.39 ( 28.68 )
        Bladder Control (n=67, 85)
    19.4 ( 29.67 )
    10.2 ( 21.22 )
    No statistical analyses for this end point

    Secondary: EuroQol 5-Dimensions (EQ-5D) Questionnaire Index

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    End point title
    EuroQol 5-Dimensions (EQ-5D) Questionnaire Index
    End point description
    The EuroQuol-5D (EQ-5D) questionnaire is a measure of health status that provides a simple descriptive profile and a single index value. The optional part of the questionnaire was not applied. The EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 items are combined to generate health profiles. These profiles were converted to a continuous single index score using a one to one matching. The lowest possible score is -0.594 (death) and the highest is 1.00 (full health). This endpoint was assessed in all subjects who were randomized to study treatment and who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to 50 months
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    69
    90
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.598 ( 0.43 )
    0.623 ( 0.36 )
    No statistical analyses for this end point

    Secondary: Number of subjects with change from baseline in work status at end of study

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    End point title
    Number of subjects with change from baseline in work status at end of study
    End point description
    Number of subjects with change from baseline in work status (working full time [FT], part-time [PT], unemployed/retired [U/R]) at end of study (EOS) (up to cut-off date, [19 Nov 2012]) was reported. For the category ‘part-time’, the following sub-categories were defined: part-time due to basic disease (PT1); part-time not due to basic disease (PT2); part-time reason not known (PT3). This endpoint was assessed in safety population which included subjects who received any dose of study treatment that is Cilengitide, Temozolomide or Radiotherapy. According to trial design safety data in trial arms (Cilengitide vs Control) were collected based on different visit frequency and different safety surveillance period.
    End point type
    Secondary
    End point timeframe
    Baseline, End of study (up to cut-off date, [19 Nov 2012])
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    263
    258
    Units: Subjects
        Baseline: FT, EOS: FT
    3
    6
        Baseline: FT, EOS: PT1
    2
    1
        Baseline: FT, EOS: PT2
    1
    0
        Baseline: FT, EOS: PT3
    0
    0
        Baseline: FT, EOS: U/R
    24
    22
        Baseline: PT1, EOS: FT
    3
    2
        Baseline: PT1, EOS: PT1
    3
    1
        Baseline: PT1, EOS: PT2
    0
    0
        Baseline: PT1, EOS: PT3
    0
    0
        Baseline: PT1, EOS: U/R
    9
    12
        Baseline: PT2, EOS: FT
    0
    1
        Baseline: PT2, EOS: PT1
    0
    0
        Baseline: PT2, EOS: PT2
    0
    0
        Baseline: PT2, EOS: PT3
    1
    0
        Baseline: PT2, EOS: U/R
    5
    4
        Baseline: PT3, EOS: FT
    0
    0
        Baseline: PT3, EOS: PT1
    0
    0
        Baseline: PT3, EOS: PT2
    0
    0
        Baseline: PT3, EOS: PT3
    0
    0
        Baseline: PT3, EOS: U/R
    0
    0
        Baseline: U/R, EOS: FT
    5
    8
        Baseline: U/R, EOS: PT1
    5
    7
        Baseline: U/R, EOS: PT2
    1
    1
        Baseline: U/R, EOS: PT3
    0
    0
        Baseline: U/R, EOS: U/R
    199
    191
        Baseline: Missing, EOS: FT
    0
    0
        Baseline: Missing, EOS: PT1
    0
    0
        Baseline: Missing, EOS: PT2
    0
    0
        Baseline: Missing, EOS: PT3
    0
    0
        Baseline: Missing, EOS: U/R
    1
    1
        Baseline: Missing, EOS: Missing
    1
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events (AEs), serious AEs, treatment-related AEs, treatment-related serious AEs, AEs leading to death, treatment related AEs leading to death, AEs of Grade 3 or 4 and treatment related AEs of Grade 3 or 4

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    End point title
    Number of subjects with adverse events (AEs), serious AEs, treatment-related AEs, treatment-related serious AEs, AEs leading to death, treatment related AEs leading to death, AEs of Grade 3 or 4 and treatment related AEs of Grade 3 or 4
    End point description
    An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. Treatment-emergent AEs are the events between first dose of study drug and up to 28 days after last dose of study treatment. A Serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-related AEs are the AEs which are suspected to be reasonably related to the study treatment (cilengitide, or radiotherapy, or temozolomide) as per investigator assessment. The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome. This endpoint was assessed in Safety population.
    End point type
    Secondary
    End point timeframe
    Time from first dose up to 28 days after last dose of study treatment, reported between day of first subject randomized, that is, Sep 2008 until cut-off date (19 Nov 2012)
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    263
    258
    Units: Subjects
        AEs
    261
    253
        Serious AEs
    138
    115
        Treatment-related AEs
    229
    222
        Treatment-Related Serious AEs
    55
    47
        AEs leading to death
    11
    9
        Treatment-related AEs leading to death
    3
    3
        AEs with NCI−CTC toxicity Grade 3 or 4
    169
    158
        Treatment-related AEs of Grade 3 or 4
    100
    101
    No statistical analyses for this end point

    Secondary: Number of subjects with AEs belonging to standardized medical dictionary for regulatory activities (MedDRA) queries (SMQs) thromboembolic events and haemorrhage with NCI−CTC toxicity Grade 3 or 4

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    End point title
    Number of subjects with AEs belonging to standardized medical dictionary for regulatory activities (MedDRA) queries (SMQs) thromboembolic events and haemorrhage with NCI−CTC toxicity Grade 3 or 4
    End point description
    Thromboembolic events (standardized MedDRA query [SMQ]) Grade 3 or 4 AEs encompassed hemiparesis and cerebrovascular accident, pulmonary embolism, and deep vein thrombosis. Thromboembolic events (SMQ) of any grade and of Grade 3 or 4 were generally more frequent in the Cilengitide + Temozolomide/Radiotherapy group than in the Temozolomide/Radiotherapy group but were still in the expected range of this patient population The severity of AEs was assessed according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE) (version 3.0): Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling. Note: Death (Grade 5) was regarded as an outcome. This endpoint was assessed in safety analysis population.
    End point type
    Secondary
    End point timeframe
    Time from first dose up to 28 days after last dose of study treatment, reported between day of first subject randomized, that is, Sep 2008 until cut-off date (19 Nov 2012).
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    263
    258
    Units: Subjects
        SMQ:Thromboembolic events
    35
    23
        SMQ: Haemorrhage
    4
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically significant abnormal electrocardiogram (ECG) and lab parameters

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    End point title
    Number of subjects with clinically significant abnormal electrocardiogram (ECG) and lab parameters
    End point description
    Any clinically significant abnormal ECG and lab finding was planned to be reported as AE only so they have been captured in the below mentioned adverse event section.
    End point type
    Secondary
    End point timeframe
    Up to 50 months
    End point values
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Subjects
    Notes
    [7] - Clinically significant abnormal ECG and lab finding was planned to be reported as AE only
    [8] - Clinically significant abnormal ECG and lab finding was planned to be reported as AE only
    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 participant randomized, that is, Sep 2008 until cut-off date (19 Nov 2012)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Cilengitide + Temozolomide + Radiotherapy
    Reporting group description
    Cilengitide 2000 milligram (mg) twice weekly over 1 hour intravenous infusion from Weeks -1 to 77, Temozolomide (TMZ) 75 milligram per square meter [mg/m^2] intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and radiotherapy (RTX) at a dose of 2 gray (Gy) per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason. Continuation of cilengitide treatment after Week 77 will be optional in participants without disease progression.

    Reporting group title
    Temozolomide + Radiotherapy
    Reporting group description
    TMZ 75 mg/m^2 administered intravenously once daily from Weeks 1 to 6, from Week 11 onward, TMZ was given as maintenance treatment at a dose of 150-200 mg/m^2 for consecutive 5 days every 4 weeks until Week 34 and RTX at a dose of 2 Gy per fraction once daily, 5 days per week from Weeks 1 to 6 or until occurrence of progressive disease, unacceptable toxicity, or withdrawal for any other reason.

    Serious adverse events
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    138 / 263 (52.47%)
    115 / 258 (44.57%)
         number of deaths (all causes)
    139
    130
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLIOBLASTOMA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL TUMOUR HAEMORRHAGE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO MENINGES
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEURILEMMOMA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATIC CARCINOMA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL CELL LUNG CANCER STAGE UNSPECIFIED
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    THYROID CANCER
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEOPLASM RECURRENCE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL #CYSTS AND POLYPS)
         subjects affected / exposed
    6 / 263 (2.28%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    5 / 263 (1.90%)
    6 / 258 (2.33%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLISM VENOUS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBCLAVIAN VEIN THROMBOSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    SURGERY
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PALLIATIVE CARE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLADDER CATHETERISATION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHENIA
         subjects affected / exposed
    5 / 263 (1.90%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 263 (0.76%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    GAIT DISTURBANCE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISEASE PROGRESSION
         subjects affected / exposed
    4 / 263 (1.52%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    DEVICE MALFUNCTION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    4 / 263 (1.52%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DYSPNOEA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOTHORAX
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    4 / 263 (1.52%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    VOCAL CORD POLYP
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    12 / 263 (4.56%)
    7 / 258 (2.71%)
         occurrences causally related to treatment / all
    6 / 12
    0 / 7
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    DELIRIUM
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISORIENTATION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    5 / 263 (1.90%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AGITATION
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HALLUCINATION, VISUAL
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANIC ATTACK
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERSONALITY CHANGE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSYCHOTIC DISORDER
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSTHYMIC DISORDER
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCHIZOPHRENIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    FIBRIN D DIMER INCREASED
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD URIC ACID INCREASED
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FRACTURE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIMB INJURY
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL OEDEMA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OVERDOSE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OPEN WOUND
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL BONES FRACTURE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIATION NECROSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIATION INJURY
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND COMPLICATION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY THROMBOSIS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATAXIA
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN INJURY
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN OEDEMA
         subjects affected / exposed
    5 / 263 (1.90%)
    5 / 258 (1.94%)
         occurrences causally related to treatment / all
    0 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL VENTRICLE DILATATION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL CYST
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CENTRAL NERVOUS SYSTEM NECROSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    6 / 263 (2.28%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONVULSION
         subjects affected / exposed
    20 / 263 (7.60%)
    14 / 258 (5.43%)
         occurrences causally related to treatment / all
    2 / 20
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL NERVE DISORDER
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COMA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DIZZINESS
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COORDINATION ABNORMAL
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    5 / 263 (1.90%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    12 / 263 (4.56%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL PRESSURE INCREASED
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GRAND MAL CONVULSION
         subjects affected / exposed
    5 / 263 (1.90%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NORMAL PRESSURE HYDROCEPHALUS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUROLOGICAL DECOMPENSATION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MIGRAINE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LETHARGY
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARTIAL SEIZURES
         subjects affected / exposed
    4 / 263 (1.52%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYRAMIDAL TRACT SYNDROME
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPEECH DISORDER
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST HERPETIC NEURALGIA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRIGEMINAL NEURALGIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STATUS EPILEPTICUS
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VISUAL FIELD DEFECT
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIITH NERVE PARALYSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    2 / 263 (0.76%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISSEMINATED INTRAVASCULAR COAGULATION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE BONE MARROW APLASIA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    6 / 263 (2.28%)
    11 / 258 (4.26%)
         occurrences causally related to treatment / all
    6 / 6
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    THROMBOCYTOPENIA
         subjects affected / exposed
    16 / 263 (6.08%)
    24 / 258 (9.30%)
         occurrences causally related to treatment / all
    16 / 16
    24 / 24
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    LEUKOPENIA
         subjects affected / exposed
    4 / 263 (1.52%)
    10 / 258 (3.88%)
         occurrences causally related to treatment / all
    4 / 4
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    HAEMATOTOXICITY
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOPENIA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC DISORDER
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 263 (0.76%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 263 (1.14%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC STEATOSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DRUG ERUPTION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EXFOLIATIVE RASH
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    BLADDER NECK OBSTRUCTION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CALCULUS URINARY
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCLE SPASMS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERIAL INFECTION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN ABSCESS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 263 (1.14%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 INFLUENZA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED SEPSIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPIGLOTTITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORAL CANDIDIASIS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NECROTISING FASCIITIS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    9 / 263 (3.42%)
    7 / 258 (2.71%)
         occurrences causally related to treatment / all
    3 / 9
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    2 / 2
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 263 (0.76%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND ABSCESS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    SKIN INFECTION
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TYPE 2 DIABETES MELLITUS
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERURICAEMIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cilengitide + Temozolomide + Radiotherapy Temozolomide + Radiotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    252 / 263 (95.82%)
    241 / 258 (93.41%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    17 / 263 (6.46%)
    8 / 258 (3.10%)
         occurrences all number
    17
    8
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    101 / 263 (38.40%)
    84 / 258 (32.56%)
         occurrences all number
    101
    84
    OEDEMA PERIPHERAL
         subjects affected / exposed
    36 / 263 (13.69%)
    24 / 258 (9.30%)
         occurrences all number
    36
    24
    ASTHENIA
         subjects affected / exposed
    42 / 263 (15.97%)
    20 / 258 (7.75%)
         occurrences all number
    42
    20
    PYREXIA
         subjects affected / exposed
    27 / 263 (10.27%)
    16 / 258 (6.20%)
         occurrences all number
    27
    16
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    51 / 263 (19.39%)
    23 / 258 (8.91%)
         occurrences all number
    51
    23
    DYSPNOEA
         subjects affected / exposed
    21 / 263 (7.98%)
    9 / 258 (3.49%)
         occurrences all number
    21
    9
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    20 / 263 (7.60%)
    6 / 258 (2.33%)
         occurrences all number
    20
    6
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    13 / 263 (4.94%)
    14 / 258 (5.43%)
         occurrences all number
    13
    14
    CONFUSIONAL STATE
         subjects affected / exposed
    14 / 263 (5.32%)
    12 / 258 (4.65%)
         occurrences all number
    14
    12
    DEPRESSION
         subjects affected / exposed
    19 / 263 (7.22%)
    14 / 258 (5.43%)
         occurrences all number
    19
    14
    INSOMNIA
         subjects affected / exposed
    35 / 263 (13.31%)
    24 / 258 (9.30%)
         occurrences all number
    35
    24
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    15 / 263 (5.70%)
    14 / 258 (5.43%)
         occurrences all number
    15
    14
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    21 / 263 (7.98%)
    17 / 258 (6.59%)
         occurrences all number
    21
    17
    Injury, poisoning and procedural complications
    RADIATION SKIN INJURY
         subjects affected / exposed
    20 / 263 (7.60%)
    22 / 258 (8.53%)
         occurrences all number
    20
    22
    Nervous system disorders
    CONVULSION
         subjects affected / exposed
    46 / 263 (17.49%)
    19 / 258 (7.36%)
         occurrences all number
    46
    19
    DIZZINESS
         subjects affected / exposed
    34 / 263 (12.93%)
    25 / 258 (9.69%)
         occurrences all number
    34
    25
    HEADACHE
         subjects affected / exposed
    118 / 263 (44.87%)
    88 / 258 (34.11%)
         occurrences all number
    118
    88
    HEMIPARESIS
         subjects affected / exposed
    17 / 263 (6.46%)
    11 / 258 (4.26%)
         occurrences all number
    17
    11
    APHASIA
         subjects affected / exposed
    25 / 263 (9.51%)
    11 / 258 (4.26%)
         occurrences all number
    25
    11
    MEMORY IMPAIRMENT
         subjects affected / exposed
    27 / 263 (10.27%)
    18 / 258 (6.98%)
         occurrences all number
    27
    18
    PARAESTHESIA
         subjects affected / exposed
    14 / 263 (5.32%)
    7 / 258 (2.71%)
         occurrences all number
    14
    7
    TREMOR
         subjects affected / exposed
    20 / 263 (7.60%)
    11 / 258 (4.26%)
         occurrences all number
    20
    11
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    16 / 263 (6.08%)
    17 / 258 (6.59%)
         occurrences all number
    16
    17
    NEUTROPENIA
         subjects affected / exposed
    32 / 263 (12.17%)
    23 / 258 (8.91%)
         occurrences all number
    32
    23
    LYMPHOPENIA
         subjects affected / exposed
    46 / 263 (17.49%)
    35 / 258 (13.57%)
         occurrences all number
    46
    35
    LEUKOPENIA
         subjects affected / exposed
    30 / 263 (11.41%)
    28 / 258 (10.85%)
         occurrences all number
    30
    28
    THROMBOCYTOPENIA
         subjects affected / exposed
    61 / 263 (23.19%)
    61 / 258 (23.64%)
         occurrences all number
    61
    61
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    16 / 263 (6.08%)
    11 / 258 (4.26%)
         occurrences all number
    16
    11
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    15 / 263 (5.70%)
    7 / 258 (2.71%)
         occurrences all number
    15
    7
    ABDOMINAL PAIN
         subjects affected / exposed
    16 / 263 (6.08%)
    7 / 258 (2.71%)
         occurrences all number
    16
    7
    CONSTIPATION
         subjects affected / exposed
    101 / 263 (38.40%)
    78 / 258 (30.23%)
         occurrences all number
    101
    78
    DIARRHOEA
         subjects affected / exposed
    44 / 263 (16.73%)
    20 / 258 (7.75%)
         occurrences all number
    44
    20
    DYSPEPSIA
         subjects affected / exposed
    24 / 263 (9.13%)
    8 / 258 (3.10%)
         occurrences all number
    24
    8
    VOMITING
         subjects affected / exposed
    79 / 263 (30.04%)
    86 / 258 (33.33%)
         occurrences all number
    79
    86
    NAUSEA
         subjects affected / exposed
    129 / 263 (49.05%)
    126 / 258 (48.84%)
         occurrences all number
    129
    126
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    70 / 263 (26.62%)
    70 / 258 (27.13%)
         occurrences all number
    70
    70
    RASH
         subjects affected / exposed
    28 / 263 (10.65%)
    19 / 258 (7.36%)
         occurrences all number
    28
    19
    PRURITUS
         subjects affected / exposed
    32 / 263 (12.17%)
    15 / 258 (5.81%)
         occurrences all number
    32
    15
    DRY SKIN
         subjects affected / exposed
    16 / 263 (6.08%)
    12 / 258 (4.65%)
         occurrences all number
    16
    12
    ERYTHEMA
         subjects affected / exposed
    21 / 263 (7.98%)
    10 / 258 (3.88%)
         occurrences all number
    21
    10
    Renal and urinary disorders
    URINARY INCONTINENCE
         subjects affected / exposed
    15 / 263 (5.70%)
    4 / 258 (1.55%)
         occurrences all number
    15
    4
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    25 / 263 (9.51%)
    6 / 258 (2.33%)
         occurrences all number
    25
    6
    BACK PAIN
         subjects affected / exposed
    31 / 263 (11.79%)
    8 / 258 (3.10%)
         occurrences all number
    31
    8
    MUSCULAR WEAKNESS
         subjects affected / exposed
    22 / 263 (8.37%)
    15 / 258 (5.81%)
         occurrences all number
    22
    15
    PAIN IN EXTREMITY
         subjects affected / exposed
    24 / 263 (9.13%)
    13 / 258 (5.04%)
         occurrences all number
    24
    13
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    32 / 263 (12.17%)
    11 / 258 (4.26%)
         occurrences all number
    32
    11
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    28 / 263 (10.65%)
    16 / 258 (6.20%)
         occurrences all number
    28
    16
    URINARY TRACT INFECTION
         subjects affected / exposed
    16 / 263 (6.08%)
    21 / 258 (8.14%)
         occurrences all number
    16
    21
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    54 / 263 (20.53%)
    45 / 258 (17.44%)
         occurrences all number
    54
    45
    HYPOKALAEMIA
         subjects affected / exposed
    14 / 263 (5.32%)
    8 / 258 (3.10%)
         occurrences all number
    14
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2010
    To adapt certain processes of study conduct based on the global practical experience. These included the following: The eligibility decision could be based on local laboratory blood results if the process time for the central laboratory could result in the subject being ineligible (however the respective central laboratory tests still to be performed) The detailed time windows from screening to randomization were revised to allow more flexibility. The inclusion criterion “normal PTT” was revised to “below ULN PTT”. Based on updated safety data in newly diagnosed GBM patients and in alignment with other recently initiated study protocols of cilengitide combination treatments (EMR 200052-013 and EMR 200037-014), a case-by-case decision was allowed to potentially use therapeutic doses of heparin (after initial resolution of a disease-related thromboembolic event, e.g., a DVT) with cilengitide treatment after resolution of the event. To introduce a general description of cilengitide handling independent of dose strength by referring to the handling instructions. To adapt the technical cut-off value of the applied MGMT assay to reflect the technical modalities of this assay version based on the current data set (actual nadir of the bimodal distribution). To include minor corrections and clarifications to the protocol.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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