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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo Controlled, Multicenter Phase III Trial of Bevacizumab, Temozolomide and Radiotherapy, Followed by Bevacizumab and Temozolomide Versus Placebo, Temozolomide and Radiotherapy Followed by Placebo and Temozolomide in Patients With Newly Diagnosed Glioblastoma

    Summary
    EudraCT number
    2008-006146-26
    Trial protocol
    FR   PT   DE   GB   BE   ES   HU   NL   SE   DK   IT   GR  
    Global end of trial date
    08 Sep 2015

    Results information
    Results version number
    v3(current)
    This version publication date
    10 Sep 2017
    First version publication date
    15 Mar 2015
    Other versions
    v1 (removed from public view) , v2
    Version creation reason
    Summary report(s)
    BO21990 CTg receipt

    Trial information

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    Trial identification
    Sponsor protocol code
    BO21990
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00943826
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, 41 61 6878333, global.trial_information@roche.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
    08 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To demonstrate the superiority in overall survival (OS) when bevacizumab is added to temozolomide with radiotherapy followed by temozolomide for the treatment of subjects with newly diagnosed glioblastoma • To demonstrate the superiority in progression-free survival (PFS) (using adapted MacDonald criteria) when bevacizumab is added to temozolomide with radiotherapy followed by temozolomide for the treatment of subjects with newly diagnosed glioblastoma
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP), or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the subject. The protocol and its amendments were approved by Independent Ethics Committees/Institutional review boards and written informed consent was obtained from each subject participating in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 May 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    31 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Sweden: 30
    Country: Number of subjects enrolled
    United Kingdom: 47
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Australia: 61
    Country: Number of subjects enrolled
    Belgium: 36
    Country: Number of subjects enrolled
    Canada: 95
    Country: Number of subjects enrolled
    Denmark: 26
    Country: Number of subjects enrolled
    France: 145
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Japan: 44
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    New Zealand: 30
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Portugal: 29
    Country: Number of subjects enrolled
    Romania: 66
    Country: Number of subjects enrolled
    Russian Federation: 39
    Worldwide total number of subjects
    921
    EEA total number of subjects
    575
    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)
    721
    From 65 to 84 years
    200
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1087 subjects were screened, out of which 921 subjects were randomized to the study treatment.

    Period 1
    Period 1 title
    Concurrent Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bevacizumab + RT + Temozolomide
    Arm description
    In the Concurrent Phase subjects received radiotherapy (RT) in daily fractions of 2 Gray (Gy) given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 milligrams per square meter (mg/m^2) daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects received bevacizumab IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received bevacizumab every 3 weeks until disease progression/unacceptable toxicity.

    Arm title
    Placebo + RT + Temozolomide
    Arm description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Number of subjects in period 1
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Started
    458
    463
    Treated
    452
    459
    Completed
    397
    421
    Not completed
    61
    42
         Refused treatment/Did not cooperate
    5
    7
         Protocol Violation
    1
    -
         Consent withdrawn by subject
    3
    7
         Adverse Events
    50
    27
         Administrative reasons
    2
    1
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bevacizumab + RT + Temozolomide
    Arm description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects received bevacizumab IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received bevacizumab every 3 weeks until disease progression/unacceptable toxicity.

    Arm title
    Placebo + RT+Temozolomide
    Arm description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Number of subjects in period 2 [1]
    Bevacizumab + RT + Temozolomide Placebo + RT+Temozolomide
    Started
    396
    370
    Completed
    353
    331
    Not completed
    43
    39
         Refused treatment/Did not cooperate
    6
    3
         Failure to return
    -
    1
         Consent withdrawn by subject
    2
    4
         Adverse Events
    31
    30
         Administrative reasons
    4
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some who completed previous period had discontinued, progressed, or died prior to this period.
    Period 3
    Period 3 title
    Monotherapy Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bevacizumab + RT + Temozolomide
    Arm description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects received bevacizumab IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received bevacizumab every 3 weeks until disease progression/unacceptable toxicity.

    Arm title
    Placebo + RT + Temozolomide
    Arm description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Number of subjects in period 3 [2]
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Started
    269
    159
    Completed
    204
    143
    Not completed
    65
    16
         Refused treatment/Did not cooperate
    8
    2
         Failure to return
    2
    1
         Consent withdrawn by subject
    2
    3
         Adverse Events
    42
    5
         Administrative reasons
    11
    5
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some who completed previous period had discontinued, progressed, or died prior to this period.
    Period 4
    Period 4 title
    After Primary Overall Survival Analysis
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bevacizumab + RT + Temozolomide
    Arm description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects received bevacizumab IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received bevacizumab every 3 weeks until disease progression/unacceptable toxicity.

    Arm title
    Placebo + RT+Temozolomide
    Arm description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase subjects placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Number of subjects in period 4 [3]
    Bevacizumab + RT + Temozolomide Placebo + RT+Temozolomide
    Started
    27
    20
    Completed
    0
    0
    Not completed
    27
    20
         Progression of Disease
    2
    4
         Consent withdrawn by subject
    4
    -
         Adverse Events
    11
    -
         Administrative reasons
    10
    16
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Some who completed previous period had discontinued, progressed, or died prior to this period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy (RT) in daily fractions of 2 Gray (Gy) given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 milligrams per square meter (mg/m^2) daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group title
    Placebo + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide Total
    Number of subjects
    458 463 921
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    55.9 (20 to 84) 55.9 (18 to 79) -
    Gender categorical
    Units: Subjects
        Female
    176 165 341
        Male
    282 298 580

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy (RT) in daily fractions of 2 Gray (Gy) given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 milligrams per square meter (mg/m^2) daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 milligrams per kilogram (mg/kg) intravenous (IV) every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group title
    Placebo + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Reporting group title
    Bevacizumab + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group title
    Placebo + RT+Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Reporting group title
    Bevacizumab + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group title
    Placebo + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.
    Reporting group title
    Bevacizumab + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group title
    Placebo + RT+Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Subject analysis set title
    Bevacizumab + RT + Temozolomide
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Subject analysis set title
    Placebo + RT + Temozolomide
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Primary: Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator

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    End point title
    Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator
    End point description
    PFS is defined as time from randomization to disease progression (PD) or death. PD was assessed using adapted Macdonald response criteria (modified World Health Organization [WHO] criteria) based on 3 components:radiological tumor assessments using Magnetic Resonance Imaging [MRI] scans,neurological assessment and changes in corticosteroid use. PD is assessed as greater than or equal to (>=) 25% increase in sum of products of the longest diameters of all index lesions(enhancing,measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing,non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment.
    End point type
    Primary
    End point timeframe
    Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    458
    463
    Units: Months
        median (confidence interval 95%)
    10.6 (10 to 11.4)
    6.2 (6 to 7.5)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bevacizumab + RT + Temozolomide v Placebo + RT + Temozolomide
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    0.74
    Notes
    [1] - Stratified by Region and Recursive partitioning analysis (RPA) Class

    Primary: Co-Primary: Overall Survival (OS)

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    End point title
    Co-Primary: Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. Intent to treat population.
    End point type
    Primary
    End point timeframe
    Randomization until OS Event [Until data cutoff= 28 February 2013 (up to 42.2 months )]
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    458
    463
    Units: Months
        median (confidence interval 95%)
    16.8 (15.5 to 18.5)
    16.7 (15.4 to 18.4)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + RT + Temozolomide v Bevacizumab + RT + Temozolomide
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0987 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.02
    Notes
    [2] - Stratified by Region and RPA Class

    Secondary: PFS as Assessed by an Independent Review Facility

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    End point title
    PFS as Assessed by an Independent Review Facility
    End point description
    An Independent Review Facility reviewed the MRI scans used by investigator to evaluate radiological tumor response. PFS is defined as time from randomization to PD or death. PD was assessed using adapted Macdonald response (modified WHO) criteria based on 3 components: radiological tumor assessments using MRI scans, neurological assessment and changes in corticosteroid use. PD is assessed as >=25% increase in sum of products of the longest diameters of all index lesions (enhancing,measurable) compared with the smallest recorded sum (nadir); or unequivocal PD of existing non-index lesions (non-enhancing and enhancing, non-measurable); or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) compared to neurological evaluation at previous disease assessment with no need for a confirmatory scan. Participants without a PFS event were censored at last disease assessment.
    End point type
    Secondary
    End point timeframe
    Randomization until PFS Event (Until data cutoff= 31 March 2012 [up to 29.5 months])
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    458
    463
    Units: Months
        median (confidence interval 95%)
    8.4 (7.9 to 9.7)
    4.3 (4.1 to 5.1)
    Statistical analysis title
    PFS as Assessed by an Independent Review Facility
    Comparison groups
    Bevacizumab + RT + Temozolomide v Placebo + RT + Temozolomide
    Number of subjects included in analysis
    921
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    0.71
    Notes
    [3] - Stratified by Region and RPA Class

    Secondary: Kaplan-Meier (KM) Estimate of One Year Overall Survival

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    End point title
    Kaplan-Meier (KM) Estimate of One Year Overall Survival
    End point description
    KM estimate of one year overall survival (probability to survive for at least 1 year) was reported. Corresponding 95% confidence interval (CI) was calculated using Greenwood’s formula. Intent to treat (ITT) population.
    End point type
    Secondary
    End point timeframe
    Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    458
    463
    Units: Probability of being alive
        number (confidence interval 95%)
    0.72 (0.68 to 0.77)
    0.66 (0.62 to 0.71)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier (KM) Estimate of Two Year Overall Survival

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    End point title
    Kaplan-Meier (KM) Estimate of Two Year Overall Survival
    End point description
    KM estimate of two year overall survival was reported (probability to survive for at least 2 years). Corresponding 95% CI was calculated using Greenwood’s formula. Intent to treat population.
    End point type
    Secondary
    End point timeframe
    Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 42.2 months])
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    458
    463
    Units: Probability of being alive
        number (confidence interval 95%)
    0.34 (0.29 to 0.38)
    0.3 (0.26 to 0.34)
    No statistical analyses for this end point

    Secondary: Duration of Stable/Improved Health Related Quality of Life (HRQoL) Using the European Organisation for Research and Treatment of Cancer Scales (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Supplemented by a Brain Cancer Module 20 (BN20)

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    End point title
    Duration of Stable/Improved Health Related Quality of Life (HRQoL) Using the European Organisation for Research and Treatment of Cancer Scales (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Supplemented by a Brain Cancer Module 20 (BN20)
    End point description
    EORTC QLQ-C30,BN20 questionnaires were used during PFS time.EORTC QLQ-C30:30-item questionnaire in 5 functional scales(physical,role,emotional,cognitive,social),3 symptoms scales,6 item measures and global health status/QoL scale.Items rated:1=not at all to 4=very much.Global health status/QoL items were rated:1=very poor to 7=excellent.The BN20:20 questions in 4 scales(future uncertainty,visual disorder,motor dysfunction,communication deficit)and 7 single-item measures rated as:1=not at all to 4=very much.All scores and single-items to a 0 to 100 scale were standardized.Stable HRQoL:Change from baseline within 10 points.Improved HRQoL:Increase of at least 10 points for functioning/global health status or decrease of at least 10 points for symptom.PFS:time from randomization to PD or death.PD:>=25% rise in SPD of longest diameters of all index lesions;or unequivocal progression of existing non-index lesions;or unequivocal 1 or more new lesions;or neurologically worsened.ITT population
    End point type
    Secondary
    End point timeframe
    Randomization until PFS Event [Until data cutoff= 31 March 2012 (up to 31.4 months)
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    458
    463
    Units: Months
    median (full range (min-max))
        Global health status
    8 (0 to 26)
    4 (1 to 29)
        Physical functioning
    7 (0 to 27)
    5 (1 to 29)
        Social functioning
    8 (0 to 26)
    4 (0 to 27)
        Motor dysfunction
    7 (1 to 27)
    4 (0 to 26)
        Communication deficit
    8 (0 to 27)
    4 (1 to 24)
    No statistical analyses for this end point

    Secondary: Number of Participants With Non-Serious Adverse Events (non-SAEs), SAEs and Death

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    End point title
    Number of Participants With Non-Serious Adverse Events (non-SAEs), SAEs and Death
    End point description
    An AE was any unfavorable and unintended sign,symptom,or disease associated with the use of the study drug,whether or not considered related to the study drug.Preexisting conditions that worsened during the study were reported as AEs.SAE is any experience that suggests a significant hazard,contraindication,side effect or precaution that:results in death,is life-threatening,required in-patient hospitalization or prolongation of existing hospitalization,results in persistent or significant disability/incapacity,is a congenital anomaly/birth defect or is medically significant.Non-SAE included all AEs except SAE(non-SAE =all AE-SAEs).Safety Population:all randomized participants who received study treatment(10 participants did not receive at least 1 dose of study treatment and were excluded,4 in Placebo & 6 in Bevacizumab.9 participants randomized to the Placebo+RT+Temozolomide arm incorrectly received at least 1 dose of bevacizumab and were added to the Bevacizumab+RT+Temozolomide arm.
    End point type
    Secondary
    End point timeframe
    Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 44.4 months])
    End point values
    Bevacizumab + RT + Temozolomide Placebo + RT + Temozolomide
    Number of subjects analysed
    461
    450
    Units: Subjects
        Non-SAEs
    437
    412
        SAEs
    179
    115
        Death
    335
    337
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization until Overall Survival Event (Until data cutoff= 28 February 2013 [up to 44.4 months])
    Adverse event reporting additional description
    Safety Population. Ten participants did not receive at least one dose of study treatment and were therefore excluded, 4 in Placebo and 6 in Bevacizumab. Nine participants randomized to the Placebo+RT+Temozolomide arm incorrectly received at least 1 dose of bevacizumab and were added to the Bevacizumab+RT+Temozolomide arm for Safety.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    Placebo + RT+Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6.1 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

    Reporting group title
    Bevacizumab + RT + Temozolomide
    Reporting group description
    In the Concurrent Phase subjects received RT in daily fractions of 2 Gy given 5 days per weeks for 6.1 weeks (for a total of 60 Gy) and temozolomide 75 mg/m^2 daily from the first day to the last day of radiotherapy (for a maximum of 49 days in case of delay to the end of radiation therapy) and bevacizumab (Avastin) 10 mg/kg IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Subjects then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The subjects then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

    Serious adverse events
    Placebo + RT+Temozolomide Bevacizumab + RT + Temozolomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    115 / 450 (25.56%)
    179 / 461 (38.83%)
         number of deaths (all causes)
    337
    336
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    6 / 450 (1.33%)
    11 / 461 (2.39%)
         occurrences causally related to treatment / all
    4 / 6
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 450 (0.22%)
    4 / 461 (0.87%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    1 / 450 (0.22%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 450 (0.67%)
    8 / 461 (1.74%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 450 (0.44%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Fatigue
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Impaired Healing
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium tremens
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Scrotal cyst
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haemorrhage
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (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 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Troponin increased
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Coronary artery stenosis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         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
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (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
    Thrombocytopenia
         subjects affected / exposed
    8 / 450 (1.78%)
    17 / 461 (3.69%)
         occurrences causally related to treatment / all
    8 / 8
    18 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 450 (0.44%)
    4 / 461 (0.87%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 450 (0.22%)
    5 / 461 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    12 / 450 (2.67%)
    13 / 461 (2.82%)
         occurrences causally related to treatment / all
    10 / 12
    13 / 13
         deaths causally related to treatment / all
    0 / 1
    2 / 2
    Lung disorder
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    convulsion
         subjects affected / exposed
    6 / 450 (1.33%)
    5 / 461 (1.08%)
         occurrences causally related to treatment / all
    4 / 6
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 450 (0.44%)
    8 / 461 (1.74%)
         occurrences causally related to treatment / all
    2 / 2
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Brain oedema
         subjects affected / exposed
    4 / 450 (0.89%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Headache
         subjects affected / exposed
    2 / 450 (0.44%)
    4 / 461 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 450 (0.44%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 450 (0.44%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal ganglia stroke
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic neuropathy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 450 (1.11%)
    5 / 461 (1.08%)
         occurrences causally related to treatment / all
    5 / 6
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 450 (0.00%)
    4 / 461 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Anal prolapse
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         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
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prurigo
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 450 (1.11%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 450 (0.67%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    3 / 450 (0.67%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 450 (1.11%)
    10 / 461 (2.17%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Sepsis
         subjects affected / exposed
    1 / 450 (0.22%)
    6 / 461 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    Brain abscess
         subjects affected / exposed
    3 / 450 (0.67%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 450 (0.67%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 450 (0.67%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 461 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infection
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 461 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopneumonia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis herpes
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 461 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Tonsilitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 461 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Placebo + RT+Temozolomide Bevacizumab + RT + Temozolomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    412 / 450 (91.56%)
    437 / 461 (94.79%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    51 / 450 (11.33%)
    175 / 461 (37.96%)
         occurrences all number
    62
    270
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    178 / 450 (39.56%)
    191 / 461 (41.43%)
         occurrences all number
    220
    277
    Asthenia
         subjects affected / exposed
    63 / 450 (14.00%)
    86 / 461 (18.66%)
         occurrences all number
    76
    107
    Oedema peripheral
         subjects affected / exposed
    34 / 450 (7.56%)
    36 / 461 (7.81%)
         occurrences all number
    42
    43
    Pyrexia
         subjects affected / exposed
    26 / 450 (5.78%)
    39 / 461 (8.46%)
         occurrences all number
    28
    50
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    42 / 450 (9.33%)
    53 / 461 (11.50%)
         occurrences all number
    46
    59
    Depression
         subjects affected / exposed
    30 / 450 (6.67%)
    43 / 461 (9.33%)
         occurrences all number
    30
    44
    Anxiety
         subjects affected / exposed
    25 / 450 (5.56%)
    29 / 461 (6.29%)
         occurrences all number
    26
    32
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    42 / 450 (9.33%)
    38 / 461 (8.24%)
         occurrences all number
    43
    38
    Investigations
    Weight decreased
         subjects affected / exposed
    18 / 450 (4.00%)
    36 / 461 (7.81%)
         occurrences all number
    19
    36
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 450 (5.56%)
    22 / 461 (4.77%)
         occurrences all number
    29
    25
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    120 / 450 (26.67%)
    148 / 461 (32.10%)
         occurrences all number
    205
    297
    Neutropenia
         subjects affected / exposed
    53 / 450 (11.78%)
    66 / 461 (14.32%)
         occurrences all number
    82
    121
    Leukopenia
         subjects affected / exposed
    40 / 450 (8.89%)
    56 / 461 (12.15%)
         occurrences all number
    84
    124
    Lymphopenia
         subjects affected / exposed
    39 / 450 (8.67%)
    34 / 461 (7.38%)
         occurrences all number
    53
    46
    Anaemia
         subjects affected / exposed
    34 / 450 (7.56%)
    27 / 461 (5.86%)
         occurrences all number
    48
    40
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    22 / 450 (4.89%)
    98 / 461 (21.26%)
         occurrences all number
    23
    140
    Cough
         subjects affected / exposed
    46 / 450 (10.22%)
    55 / 461 (11.93%)
         occurrences all number
    54
    67
    Dyspnoea
         subjects affected / exposed
    18 / 450 (4.00%)
    26 / 461 (5.64%)
         occurrences all number
    19
    30
    Oropharyngeal pain
         subjects affected / exposed
    12 / 450 (2.67%)
    29 / 461 (6.29%)
         occurrences all number
    14
    32
    Dysphonia
         subjects affected / exposed
    7 / 450 (1.56%)
    42 / 461 (9.11%)
         occurrences all number
    8
    46
    Nervous system disorders
    Headache
         subjects affected / exposed
    130 / 450 (28.89%)
    172 / 461 (37.31%)
         occurrences all number
    183
    265
    Dizziness
         subjects affected / exposed
    53 / 450 (11.78%)
    46 / 461 (9.98%)
         occurrences all number
    57
    61
    Dysgeusia
         subjects affected / exposed
    33 / 450 (7.33%)
    39 / 461 (8.46%)
         occurrences all number
    36
    43
    Convulsion
         subjects affected / exposed
    39 / 450 (8.67%)
    36 / 461 (7.81%)
         occurrences all number
    64
    60
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    191 / 450 (42.44%)
    223 / 461 (48.37%)
         occurrences all number
    278
    367
    Constipation
         subjects affected / exposed
    137 / 450 (30.44%)
    178 / 461 (38.61%)
         occurrences all number
    178
    247
    Vomiting
         subjects affected / exposed
    100 / 450 (22.22%)
    145 / 461 (31.45%)
         occurrences all number
    149
    224
    Diarrhoea
         subjects affected / exposed
    69 / 450 (15.33%)
    95 / 461 (20.61%)
         occurrences all number
    90
    149
    Abdominal pain
         subjects affected / exposed
    17 / 450 (3.78%)
    33 / 461 (7.16%)
         occurrences all number
    20
    39
    Dyspepsia
         subjects affected / exposed
    16 / 450 (3.56%)
    31 / 461 (6.72%)
         occurrences all number
    18
    37
    Abdominal pain upper
         subjects affected / exposed
    12 / 450 (2.67%)
    35 / 461 (7.59%)
         occurrences all number
    12
    39
    Gingival bleeding
         subjects affected / exposed
    6 / 450 (1.33%)
    36 / 461 (7.81%)
         occurrences all number
    8
    46
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    19 / 450 (4.22%)
    72 / 461 (15.62%)
         occurrences all number
    21
    122
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    162 / 450 (36.00%)
    180 / 461 (39.05%)
         occurrences all number
    165
    186
    Rash
         subjects affected / exposed
    60 / 450 (13.33%)
    76 / 461 (16.49%)
         occurrences all number
    81
    95
    Pruritus
         subjects affected / exposed
    37 / 450 (8.22%)
    54 / 461 (11.71%)
         occurrences all number
    44
    68
    Dry skin
         subjects affected / exposed
    24 / 450 (5.33%)
    34 / 461 (7.38%)
         occurrences all number
    25
    38
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 450 (6.67%)
    71 / 461 (15.40%)
         occurrences all number
    32
    86
    Pain in extremity
         subjects affected / exposed
    22 / 450 (4.89%)
    48 / 461 (10.41%)
         occurrences all number
    28
    54
    Back pain
         subjects affected / exposed
    29 / 450 (6.44%)
    37 / 461 (8.03%)
         occurrences all number
    32
    40
    Muscular weakness
         subjects affected / exposed
    33 / 450 (7.33%)
    29 / 461 (6.29%)
         occurrences all number
    36
    32
    Musculoskeletal pain
         subjects affected / exposed
    12 / 450 (2.67%)
    39 / 461 (8.46%)
         occurrences all number
    12
    44
    Myalgia
         subjects affected / exposed
    12 / 450 (2.67%)
    28 / 461 (6.07%)
         occurrences all number
    13
    30
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    74 / 450 (16.44%)
    116 / 461 (25.16%)
         occurrences all number
    89
    157
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 450 (5.78%)
    63 / 461 (13.67%)
         occurrences all number
    50
    90
    Urinary tract infection
         subjects affected / exposed
    27 / 450 (6.00%)
    49 / 461 (10.63%)
         occurrences all number
    31
    70
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 450 (2.89%)
    31 / 461 (6.72%)
         occurrences all number
    16
    40

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2010
    An additional interim analysis was introduced to be triggered when approximately 50% of the deaths required for the final OS analysis had occurred. In the statistical plan, the difference between the arms for the 1-year and 2-year OS rates was tested using a z test rather than a Cochran Mantel Haenzel test.
    28 Aug 2012
    The amendment ensured continuity of Bevacizumab treatment for those subjects still on active treatment at the time of final unblinding at the sites (after the final OS analysis). Data collection was restricted to the reporting of related SAEs and adverse events of special interest (AESIs) via the SAE forms only. At the time of the treatment allocation unblinding, all subjects receiving placebo were discontinued from study treatment. Safety data was to be collected for 90 days (AEs), 183 days (AESI), or indefinitely (relates SAEs) following the last administration of study treatment.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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