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    Clinical Trial Results:
    A randomized, open-label, multi-center Phase II trial of bevacizumab and radiotherapy fol-lowed by bevacizumab and irinotecan vs. temozolomide and radiotherapy followed by temo-zolomide monotherapy in patients with newly diagnosed glioblastoma and a non-methylated MGMT-promoter (GLARIUS)

    Summary
    EudraCT number
    		 2009-010390-21
    Trial protocol
    		 DE  
    Global end of trial date
    24 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Feb 2016
    First version publication date
    25 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML21965
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00967330
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +49 41616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +49 41616878333, 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
    24 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This randomized, open-label, multi-center Phase II trial was intended to investigate the efficacy and safety of bevacizumab and radiotherapy followed by bevacizumab and irinotecan (BEV/IRI) as compared with temozolomide (TMZ) and radiotherapy followed by 6 courses of maintenance with TMZ.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) standards and according to the all local laws and regulations concerning clinical study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 182
    Worldwide total number of subjects
    182
    EEA total number of subjects
    182
    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)
    144
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening was done from Day 1-28 after resection.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bevacizumab + Irinotecan
    Arm description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gray (Gy) given 5 fractions per week for 6 to 7 weeks and intravenous infusion (IV) of bevacizumab (BEV) 10 milligrams per kilogram (mg/kg) body weight every 14 ± 2 days starting during the first week to the last week of radiotherapy. Participants then entered the Maintenance Phase where they received BEV 10 mg/kg body weight and IV irinotecan (IRI) 125 milligrams per square meter (mg/m^2) body surface area (BSA) or 340 mg/m^2 BSA in participants not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or receiving EIAEDs, respectively for every 14± 2 days until progressive disease (PD) or for a maximum treatment period of 2 years after inclusion of the last participant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gy given 5 fractions per week for 6 to 7 weeks and IV infusion of BEV 10 mg/kg body weight every 14 ± 2 days starting during the first week to the last week of radiotherapy.

    Arm title
    		 Temozolomide
    Arm description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gy given 5 fractions per week for 6 to 7 week and temozolomide (TMZ) capsule 75 mg/m^2 BSA daily from the first day to the last day of radiotherapy . There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of TMZ 150 to 200 mg/m^2 BSA daily in the first 5 days of each cycle until PD or for a maximum treatment period of 2 years after inclusion of the last participant. Only participants with progressive disease during or after TMZ therapy could receive bevacizumab (BEV)/irinotecan (IRI) or BEV monotherapy as optional second-line study therapy at the discretion of the investigator, if eligible.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gy given 5 fractions per week for 6 to 7 week and TMZ capsule 75 mg/m^2 BSA daily from the first day to the last day of radiotherapy . There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of TMZ 150 to 200 mg/m^2 BSA daily in the first 5 days of each cycle until PD or for a maximum treatment period of 2 years after inclusion of the last participant.

    Number of subjects in period 1
    		Bevacizumab + Irinotecan Temozolomide
    Started
    122
    60
    Completed
    0
    0
    Not completed
    122
    60
         Adverse event, serious fatal
    102
    51
         Consent withdrawn by subject
    6
    -
         Regular
    10
    3
         Does not meet Inclusion-Exclusion criteria
    3
    4
         Lost to follow-up
    1
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + Irinotecan
    Reporting group description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gray (Gy) given 5 fractions per week for 6 to 7 weeks and intravenous infusion (IV) of bevacizumab (BEV) 10 milligrams per kilogram (mg/kg) body weight every 14 ± 2 days starting during the first week to the last week of radiotherapy. Participants then entered the Maintenance Phase where they received BEV 10 mg/kg body weight and IV irinotecan (IRI) 125 milligrams per square meter (mg/m^2) body surface area (BSA) or 340 mg/m^2 BSA in participants not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or receiving EIAEDs, respectively for every 14± 2 days until progressive disease (PD) or for a maximum treatment period of 2 years after inclusion of the last participant.

    Reporting group title
    Temozolomide
    Reporting group description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gy given 5 fractions per week for 6 to 7 week and temozolomide (TMZ) capsule 75 mg/m^2 BSA daily from the first day to the last day of radiotherapy . There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of TMZ 150 to 200 mg/m^2 BSA daily in the first 5 days of each cycle until PD or for a maximum treatment period of 2 years after inclusion of the last participant. Only participants with progressive disease during or after TMZ therapy could receive bevacizumab (BEV)/irinotecan (IRI) or BEV monotherapy as optional second-line study therapy at the discretion of the investigator, if eligible.

    Reporting group values
    		 Bevacizumab + Irinotecan Temozolomide Total
    Number of subjects
    		 122 60 182
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.4 ( 10.17 ) 56.4 ( 10.84 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 21 60
        Male
    		 83 39 122

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + Irinotecan
    Reporting group description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gray (Gy) given 5 fractions per week for 6 to 7 weeks and intravenous infusion (IV) of bevacizumab (BEV) 10 milligrams per kilogram (mg/kg) body weight every 14 ± 2 days starting during the first week to the last week of radiotherapy. Participants then entered the Maintenance Phase where they received BEV 10 mg/kg body weight and IV irinotecan (IRI) 125 milligrams per square meter (mg/m^2) body surface area (BSA) or 340 mg/m^2 BSA in participants not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or receiving EIAEDs, respectively for every 14± 2 days until progressive disease (PD) or for a maximum treatment period of 2 years after inclusion of the last participant.

    Reporting group title
    Temozolomide
    Reporting group description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gy given 5 fractions per week for 6 to 7 week and temozolomide (TMZ) capsule 75 mg/m^2 BSA daily from the first day to the last day of radiotherapy . There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of TMZ 150 to 200 mg/m^2 BSA daily in the first 5 days of each cycle until PD or for a maximum treatment period of 2 years after inclusion of the last participant. Only participants with progressive disease during or after TMZ therapy could receive bevacizumab (BEV)/irinotecan (IRI) or BEV monotherapy as optional second-line study therapy at the discretion of the investigator, if eligible.

    Primary: Percentage of Participants Achieving Progression-Free Survival (PFS) Without Disease Progression or Death at 6 Months

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    End point title
    		 Percentage of Participants Achieving Progression-Free Survival (PFS) Without Disease Progression or Death at 6 Months
    End point description
    Progression-free survival was defined as the time from randomization to objective tumor progression or death from any cause, whichever came first. Progression was defined as 25 percent (%) increase in size of enhancing tumor or any new tumor on gadolinium contrast agent magnetic resonance imaging (Gd-MRI) scans, or neurologically worse, and steroids stable or increased. Percentage of participants with achieving PFS without disease progression or death was reported. Intent-to-treat (ITT) population included participants randomized for whom it cannot be ruled out, that they took study medication at least once and where primary variable was measured at least once under study medication. Data were analyzed according to the treatment randomized (as randomized).
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: Percentage of Participants
        number (confidence interval 95%)
    79.31 (68.859 to 84.617)
    42.59 (26.68 to 53.05)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    Progression-free survival was defined as the time from randomization to objective tumor progression or death from any cause, whichever came first. Progression was defined as 25% increase in size of enhancing tumor or any new tumor on Gd-MRI scans, or neurologically worse, and steroids stable or increased. PFS was estimated using Kaplan-Meier method. ITT population. Data were analyzed according to the treatment randomized (as randomized).
    End point type
    Secondary
    End point timeframe
    From baseline to the end of the study (up to 4.5 years)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: Months
        median (full range (min-max))
    9.74 (8.72 to 10.76)
    5.99 (2.73 to 6.15)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0012
    Method
    		 Chi-squared
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.588
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.423
         upper limit
    		 0.817

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time from randomization to death from any cause. OS was estimated using Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From baseline until death (up to 4.5 years)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: Months
        median (full range (min-max))
    16.64 (15.43 to 18.36)
    17.3 (14.77 to 20.36)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8283
    Method
    		 Chi-squared
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.963
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.684
         upper limit
    		 1.354

    Secondary: Percentage of Participants Who Discontinued

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    End point title
    		 Percentage of Participants Who Discontinued
    End point description
    Discontinuation was defined as the percentage of participants who permanently discontinued treatment in either treatment arm. Percentage of participant with individual discontinuation reason are reported. CNS: central nervous system; CTCAE: Common Terminology Criteria for Adverse Events . Other reason refers to any other reason than the specified ones. ITT population.
    End point type
    Secondary
    End point timeframe
    From baseline until end of study (up to 4.5 years)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: Percentage of participants
    number (not applicable)
        Persisting non-hematological toxicity CTCAE Grade3
    0
    1.9
        CNS hemorrhagic event (CTCAE Grade >1)
    0.9
    0
        Gastro-intestinal perforation (CTCAE Grade 1-4)
    0.9
    0
        Other
    9.5
    5.6
        Participant’s wish
    6
    5.6
        Progressive disease
    74.1
    57.4
        Proteinuria (nephrotic syndrome) (CTCAE Grade 4)
    0.9
    0
        Regular
    1.7
    27.8
        Repeated CTCAE Grade 4 hematological toxicity
    0
    0.9
        Venous thrombosis/embolism
    0.9
    0
        Wound dehiscence requiring medical intervention
    0.9
    0
        Wound dehiscence requiring surgical intervention
    4.3
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With A Best Overall Response (BOR) of Complete Response (CR) and With A BOR of CR or Partial Response (PR)

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    End point title
    		 Number of Participants With A Best Overall Response (BOR) of Complete Response (CR) and With A BOR of CR or Partial Response (PR)
    End point description
    BOR was defined as the best response observed for a participant during assessment. Number of participants who had BOR as CR and number of participants who had BOR as CR or PR were reported. Complete response was defined as disappearance of all enhancing tumor on consecutive Gd-MRI scans at least 1 month apart, off steroids, and neurologically stable or improved. Partial response was defined as 50% reduction in size of enhancing tumor on consecutive Gd-MRI scans at least 1 month apart, steroids stable or reduced, and neurologically stable or improved. ITT population. Data were analyzed according to the treatment randomized (as randomized). Here, number of participants analyzed = participants who were evaluable for this outcome and n = participants who were evaluable of specified time-point.
    End point type
    Secondary
    End point timeframe
    4 week after radiotherapy (RT) (up to Week 4), >4 Week after RT (up to Week 8) and Month 6.
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    110
    46
    Units: Participants
    number (not applicable)
        CR at 4 weeks after RT (n=110,46)
    11
    2
        CR at >4 weeks after RT (n=95,35)
    11
    1
        CR at Month 6 (n=91,28)
    3
    1
        CR or PR at 4 Week after RT (n=110,46)
    42
    6
        CR or PR at >4 Week after RT (n=95,35)
    18
    3
        CR or PR at Month 6 (n=91,28)
    5
    3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.34745
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.14
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.17923
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.17
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.08
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0021
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.38
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.18761
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.23
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.38974
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.07

    Secondary: Percentage of Participants With Response on FLAIR Imaging

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    End point title
    		 Percentage of Participants With Response on FLAIR Imaging
    End point description
    FLAIR lesions were determined as “initial”, “stable”, “progressive” or “decreased”. FLAIR lesions was determined as “progressive” only if they were not be attributed to causes apart from tumor infiltration (sequelae of radiation therapy, demyelination, ischemia, infection, seizures, or other treatment effects). Percentage of participants are based on ITT population. Here, n = participants with at least 1 assessment during specified time-point. Dis.=Discontinuation.
    End point type
    Secondary
    End point timeframe
    At screening, Baseline, Month 6 and Therapy Discontinuation (Up to 4.5 years)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: Percentage of participant
    number (not applicable)
        Screening: Initial Flair Lesion (n=116,54)
    72.4
    72.2
        Screening:Stable Flair Lesion (n=116,54)
    17.2
    16.7
        Baseline:Decreased FLAIR Lesions (n=105,46)
    16.4
    20.4
        Baseline:Initial FLAIR Lesions (n=105,46)
    18.1
    18.5
        Baseline:Progressive FLAIR Lesions (n=105,46)
    14.7
    11.1
        Baseline: Stable FLAIR Lesions (n=105,46)
    41.4
    35.2
        Month 6:Progressive FLAIR Lesions (n=91,28)
    16.4
    22.2
        Month 6: Stable FLAIR Lesions (n=91,28)
    62.1
    29.6
        Therapy Dis.:Decreased FLAIR Lesions (n=55,31)
    0.9
    0
        Therapy Dis.:Progressiv FLAIR Lesions (n=55,31) 29
    29.3
    27.8
        Therapy Dis.:Stable FLAIR Lesions (n=55,31)
    17.2
    29.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ - C30) at Baseline, Post-Baseline (up to Month 30)

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ - C30) at Baseline, Post-Baseline (up to Month 30)
    End point description
    The EORTC QLQ-C30 incorporates: 5 functional scales (physical, role, cognitive, emotional, and social); 9 symptom scales (fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties); and a global health and quality-of-life scale. Most questions used 4 point scale (1 ‘Not at all’ to 4 ‘Very much’; 2 questions used 7-point scale (1 ‘very poor’ to 7 ‘Excellent’). Scores were averaged and transformed to 0-100 scale; higher score for Global Qol/functional scales=better level of functioning or a higher score for symptom scale=greater degree of symptoms. The change in global health status was determined to be the difference in values at baseline and each specific visit. The term ‘’baseline’’ refers to the time of randomization to the maintenance phase. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Post-Baseline (up to Month 30).
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Physical Functioning
    -8.3513 (-11.8714 to -4.8312)
    -6.2511 (-11.213 to -1.2892)
        Role Functioning
    -0.7635 (-6.1695 to 4.6425)
    -2.2339 (-9.9836 to 5.5159)
        Emotional Functioning
    2.2774 (-1.7409 to 6.2958)
    2.2547 (-3.4834 to 7.9928)
        Cognitive Functioning
    -2.0188 (-6.2256 to 2.188)
    -3.8401 (-9.8118 to 2.1317)
        Social Functioning
    -6.2324 (-11.348 to -1.1169)
    -4.6198 (-11.9009 to 2.6613)
        Global health Status /QoL (ql)
    -3.1134 (-6.5412 to 0.3145)
    0.3855 (-4.422 to 5.193)
        Fatique
    5.5228 (1.6424 to 9.4031)
    2.1779 (-3.322 to 7.6781)
        Nausea/Vomitting
    8.9557 (6.5139 to 11.3974)
    4.7597 (1.3958 to 8.1235)
        Pain
    10.6876 (5.8004 to 15.5747)
    1.5926 (-5.3301 to 8.5152)
        Dyspnoea
    3.7134 (-0.3957 to 7.8226)
    0.5046 (-5.2542 to 6.2635)
        Insomnia
    -2.6266 (-7.8402 to 2.587)
    -7.5026 (-14.8641 to -0.1411)
        Appetite loss
    13.7423 (9.9118 to 17.5727)
    10.9601 (5.6151 to 16.3051)
        Constipation
    8.023 (3.9214 to 12.1246)
    4.0855 (-1.6913 to 9.8624)
        Diarrhoea
    6.023 (2.9313 to 9.1147)
    -0.1455 (-4.3834 to 4.0925)
        Financial Problems
    4.8435 (0.03603 to 9.651)
    2.114 (-4.7005 to 8.9284)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4975
    Method
    		 ANOVA
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    2.1002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9855
         upper limit
    		 8.186
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.76
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4704
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9358
         upper limit
    		 7.9951
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9949
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.02278
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.035
         upper limit
    		 6.9895
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6253
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.8213
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.155
         upper limit
    		 5.5125
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7219
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.6126
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2953
         upper limit
    		 10.5205
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2443
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.4989
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4046
         upper limit
    		 9.4023
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3287
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.3449
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.0739
         upper limit
    		 3.3841
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0485
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.196
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3635
         upper limit
    		 -0.0285
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0354
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -9.095
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.5629
         upper limit
    		 -0.6271
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3724
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.2088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2784
         upper limit
    		 3.8608
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2884
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.876
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.9002
         upper limit
    		 4.1482
    Statistical analysis title
    		 Statistical Analysis 12
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4081
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.782
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3926
         upper limit
    		 3.8282
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.275
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.9375
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.0245
         upper limit
    		 3.1495
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0213
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -6.1685
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.4129
         upper limit
    		 -0.9241
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5201
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.7295
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.0727
         upper limit
    		 5.6137

    Secondary: Change From Baseline for EORTC QLQ Brain Neoplasm 20 (BN20) at Baseline, Post-Baseline (up to Month 30)

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    End point title
    		 Change From Baseline for EORTC QLQ Brain Neoplasm 20 (BN20) at Baseline, Post-Baseline (up to Month 30)
    End point description
    EORTC QLQ-BN20 consisted of 20 items assessing visual disorders, motor dysfunction, communication deficit, various disease symptoms (e.g. headaches and seizures), treatment toxicities (e.g. hair loss) and future uncertainty. All of the 20 items are rated on a 4 point Likert scale from 1=not at all, 2=a little, 3=quite a bit and 4=very much, and were linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Post-Baseline (up to Month 30)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Future uncertainty
    -5.2779 (-9.2589 to -1.2968)
    -8.5478 (-14.3337 to -2.7619)
        Visual disorder
    -2.0869 (-4.5092 to 0.3354)
    -3.202 (-6.7584 to 0.3528)
        Motor dysfunction
    5.4416 (2.3943 to 8.4888)
    6.5429 (2.1426 to 10.9433)
        Communication deficit
    4.744 (1.6899 to 7.798)
    4.6431 (0.2253 to 9.0609)
        Headaches
    4.3905 (0.6465 to 8.1345)
    -3.9389 (-9.2879 to 1.4101)
        Drowsines
    11.7204 (7.6425 to 15.7983)
    8.2805 (2.3973 to 14.1637)
        Hair loss
    11.9235 (7.6344 to 16.2127)
    7.3328 (1.0111 to 13.6545)
        Itchy skin
    5.4882 (2.0875 to 8.889)
    6.469 (1.5048 to 11.4331)
        Weakness of legs
    8.9586 (4.9123 to 13.0048)
    7.9245 (2.0687 to 13.7804)
        Bladder control
    1.502 (-1.0917 to 4.0957)
    1.971 (-1.8122 to 5.7543)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3613
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.2699
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2983
         upper limit
    		 3.7585
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6146
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.1159
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4654
         upper limit
    		 3.2336
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.686
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.1014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2449
         upper limit
    		 6.4477
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9706
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.468
         upper limit
    		 5.2663
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0124
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -8.3294
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.855
         upper limit
    		 -1.8037
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5997
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.0054
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7654
         upper limit
    		 2.7545
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3458
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.4399
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.6002
         upper limit
    		 3.7204
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2383
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.5908
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.2279
         upper limit
    		 3.0464
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7491
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.9807
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.0373
         upper limit
    		 6.9988
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7755
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.0341
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1508
         upper limit
    		 6.0827
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.841
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.469
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1211
         upper limit
    		 5.0591

    Secondary: Change From Baseline for Mini-Mental Status Examination (MMSE) at Baseline, Post-Baseline (up to Month 30)

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    End point title
    		 Change From Baseline for Mini-Mental Status Examination (MMSE) at Baseline, Post-Baseline (up to Month 30)
    End point description
    The MMSE briefly measures orientation to time and place, immediate recall, short-term verbal memory, calculation, language and construct ability. Each area tested had a designated point value, the total score can range from 0 to 30, with a higher score indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline, Post-Baseline (up to Month 30)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: units on a scale
    least squares mean (confidence interval 95%)
        Orientation to time and place
    -0.01771 (-0.1406 to 0.1052)
    -0.211 (-0.3907 to -0.03135)
        Immediate recall
    -0.00264 (-0.02163 to 0.01635)
    -0.03219 (-0.05888 to -0.00551)
        Repetitions required
    -0.05763 (-0.1971 to 0.0818)
    0.0853 (-0.1212 to 0.2918)
        Calculations
    -0.2153 (-0.3911 to -0.03952)
    -0.212 (-0.4706 to 0.04652)
        Short-term verbal memory
    0.2012 (0.106 to 0.2964)
    0.1634 (0.02332 to 0.3034)
        Language and construct ability
    -0.1254 (-0.2416 to -0.00908)
    -0.2057 (-0.3765 to -0.03499)
        Total Score
    -0.2871 (-0.7647 to 0.1905)
    -0.5999 (-1.3069 to 0.1071)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0817
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.1933
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.411
         upper limit
    		 0.02438
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0773
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.02955
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06234
         upper limit
    		 0.003241
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2608
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.1429
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1065
         upper limit
    		 0.3924
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9836
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.003262
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3092
         upper limit
    		 0.3158
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.661
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.03782
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2071
         upper limit
    		 0.1315
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4464
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.08037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2875
         upper limit
    		 0.1268
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Bevacizumab + Irinotecan v Temozolomide
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4717
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.3128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1658
         upper limit
    		 0.5402

    Secondary: Change From Baseline for Karnofsky Performance Status (KPS) Score at Baseline, Post-Baseline (up to Month 30)

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    End point title
    		 Change From Baseline for Karnofsky Performance Status (KPS) Score at Baseline, Post-Baseline (up to Month 30)
    End point description
    KPS is an 11-level score (0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100) which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Deterioration in KPS was defined as decrease of 20 or more points in KPS score. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Post-Baseline (up to Month 30)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    116
    54
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -3.3399 (-5.2132 to -1.4666)
    -5.4909 (-8.2693 to -2.7126)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Temozolomide v Bevacizumab + Irinotecan
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2078
    Method
    		 ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4983
         upper limit
    		 1.1963

    Secondary: Percentage of Participants Who Received Corticosteroid for Glioblastoma

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    End point title
    		 Percentage of Participants Who Received Corticosteroid for Glioblastoma
    End point description
    Participants used corticosteroids for the glioblastoma condition. Corticosteroids included dexamethasone, methylprednisone, fortecortin, hydrocortisone, urbason, and prednisolone. Safety population was used for this analysis. The safety population (SAF) was defined to include all participants who received at least 1 dose of study medication. Data were analyzed according to the treatment actually received (as treated).
    End point type
    Secondary
    End point timeframe
    From baseline to Month 6
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    119
    55
    Units: percentage of participants
        number (not applicable)
    80
    78.7
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    The data “99999” signifies data not available as no data collected for the specified arm. Data for time to treatment failure were not collected as this outcome was removed as per changes in planned analysis.
    End point type
    Secondary
    End point timeframe
    From baseline until end of study (up to 4.5 years)
    End point values
    		 Bevacizumab + Irinotecan Temozolomide
    Number of subjects analysed
    119
    55
    Units: months
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to the end of the study (up to 4.5 years)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Bevacizumab + Irinotecan
    Reporting group description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gray (Gy) given 5 fractions per week for 6 to 7 weeks and intravenous infusion (IV) of bevacizumab (BEV) 10 milligrams per kilogram (mg/kg) body weight every 14 ± 2 days starting during the first week to the last week of radiotherapy. Participants then entered the Maintenance Phase where they received BEV 10 mg/kg body weight and IV irinotecan (IRI) 125 milligrams per square meter (mg/m^2) body surface area (BSA) or 340 mg/m^2 BSA in participants not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or receiving EIAEDs, respectively for every 14± 2 days until progressive disease (PD) or for a maximum treatment period of 2 years after inclusion of the last participant.

    Reporting group title
    Temozolomide
    Reporting group description
    		 In the Concurrent Phase participants received radiotherapy in daily fractions of 1.8 to 2 Gy given 5 fractions per week for 6 to 7 week and temozolomide (TMZ) capsule 75 mg/m^2 BSA daily from the first day to the last day of radiotherapy . There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of TMZ 150 to 200 mg/m^2 BSA daily in the first 5 days of each cycle until PD or for a maximum treatment period of 2 years after inclusion of the last participant. Only participants with progressive disease during or after TMZ therapy could receive bevacizumab (BEV)/irinotecan (IRI) or BEV monotherapy as optional second-line study therapy at the discretion of the investigator, if eligible.

    Serious adverse events
    		 Bevacizumab + Irinotecan Temozolomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    86 / 119 (72.27%)
    46 / 55 (83.64%)
         number of deaths (all causes)
    102
    51
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to meninges
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Therapeutic procedure
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    41 / 119 (34.45%)
    20 / 55 (36.36%)
         occurrences causally related to treatment / all
    1 / 47
    0 / 22
         deaths causally related to treatment / all
    1 / 29
    0 / 14
    Hernia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    2 / 119 (1.68%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 119 (0.00%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Oedema
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 119 (2.52%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fistula
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder due to a general medical condition
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 119 (0.84%)
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (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
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 119 (0.00%)
    4 / 55 (7.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 119 (1.68%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Complex partial seizures
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    17 / 119 (14.29%)
    9 / 55 (16.36%)
         occurrences causally related to treatment / all
    0 / 30
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    6 / 119 (5.04%)
    6 / 55 (10.91%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    5 / 119 (4.20%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 119 (1.68%)
    4 / 55 (7.27%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 119 (0.84%)
    4 / 55 (7.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         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
    2 / 119 (1.68%)
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postictal paralysis
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 119 (0.84%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 119 (3.36%)
    5 / 55 (9.09%)
         occurrences causally related to treatment / all
    1 / 5
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Nausea
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis glandularis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         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
    Back pain
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bone abscess
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (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 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 119 (2.52%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 119 (2.52%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 119 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urosepsis
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    3 / 119 (2.52%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 119 (0.84%)
    0 / 55 (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
    2 / 119 (1.68%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 119 (0.84%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab + Irinotecan Temozolomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 119 (89.92%)
    37 / 55 (67.27%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    60 / 119 (50.42%)
    22 / 55 (40.00%)
         occurrences all number
    128
    51
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    54 / 119 (45.38%)
    8 / 55 (14.55%)
         occurrences all number
    119
    8
    Nausea
         subjects affected / exposed
    88 / 119 (73.95%)
    28 / 55 (50.91%)
         occurrences all number
    215
    69

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2010
    Amendment No.1, Protocol Version 2.0 (27 Oct 2010) was made in order to: Clarify the defined study procedures and time points; Revise the study flowchart; Ensure consistency between the study flow chart and the text describing the study visits; Ensure consistency between study protocol and other study documents, i.e., DSMB charter; Finally, minor typos or inconsistencies were corrected within this Amendment.
    31 Aug 2011
    Amendment No.2, Protocol Version 3.0 (31 Aug 2011) was made in order to: Document prolongation of recruitment phase; Allow for involvement of additional sites; Clarify study procedures; Update safety information according to new SmPCs.
    18 Apr 2013
    Amendment No.3, Protocol Version 4.0 (18 Apr 2013) was made in order to: Update responsible study personnel; Add evaluation in follow-up period; Revise the study flowchart; Clarify the defined study procedures.
    14 Oct 2013
    Amendment No.4, Protocol Version 5.0 (14 Oct 2013) was made in order to: Add biomarker analysis; Add evaluation in treatment period; Revise the study flowchart; Clarify the defined study procedures; Clarify statistical part of protocol.
    27 Aug 2014
    Amendment No.5, Protocol Version 6.0 (27 Aug 2014) was made in order to amend post-trial provision of care.

    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.
    Data for time to treatment failure were not collected as this outcome was removed as per changes in planned analysis.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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