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    Clinical Trial Results:
    A Randomized Phase 3 Open Label Study of Nivolumab vs Temozolomide Each in Combination With Radiation Therapy in Newly Diagnosed Adult Subjects With Unmethylated MGMT (Tumor O-6-methylguanine DNA Methyltransferase) Glioblastoma (CheckMate 498: CHECKpoint Pathway and Nivolumab Clinical Trial Evaluation 498)

    Summary
    EudraCT number
    		 2015-003739-37
    Trial protocol
    		 NL   AT   BE   DE   SE   ES   PL   DK   GB   IT  
    Global end of trial date
    04 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Mar 2023
    First version publication date
    19 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-498
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02617589
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    04 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess safety and long-term efficacy of nivolumab plus radiation therapy vs temozolomide plus radiation therapy in participants with newly diagnosed, unmethylated enzyme O-6-methyguanine DNA methyltransferase (MGMT) glioblastoma (GBM) after surgical resection.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 86
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Netherlands: 28
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    United States: 127
    Worldwide total number of subjects
    560
    EEA total number of subjects
    310
    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)
    397
    From 65 to 84 years
    163
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 560 participants were randomized and 553 treated.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab + Radiation Therapy
    Arm description
    		 Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously

    Arm title
    		 Temozolomide + Radiation Therapy
    Arm description
    		 Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally

    Number of subjects in period 1
    		Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Started
    280
    280
    Completed
    278
    275
    Not completed
    2
    5
         Request to discontinue study treatment
    1
    3
         Participant Withdrew Consent
    1
    2
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab + Radiation Therapy
    Arm description
    		 Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously

    Arm title
    		 Temozolomide + Radiation Therapy
    Arm description
    		 Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally

    Number of subjects in period 2
    		Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Started
    278
    275
    Completed
    0
    76
    Not completed
    278
    199
         Adverse event, serious fatal
    1
    1
         Poor/Non compliance
    1
    1
         Other Reasons
    3
    3
         Participant Request to discontinue
    12
    21
         Maximum Clinical Benefit
    -
    2
         Adverse event unrelated to study drug
    16
    9
         Study Drug Toxicity
    27
    20
         Participant Withdrew Consent
    2
    6
         Disease Progression
    216
    136

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab + Radiation Therapy
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously

    Reporting group title
    Temozolomide + Radiation Therapy
    Reporting group description
    		 Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally

    Reporting group values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy Total
    Number of subjects
    		 280 280 560
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 190 207 397
        From 65-84 years
    		 90 73 163
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.8 ± 10.8 56.5 ± 11.3 -
    Sex: Female, Male
    Units: Participants
        Female
    		 90 105 195
        Male
    		 190 175 365
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 231 240 471
        Black or African American
    		 4 3 7
        Asian
    		 33 28 61
        Other
    		 12 9 21
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 5
        Not Hispanic or Latino
    		 112 95 207
        Unknown or Not Reported
    		 165 183 348

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab + Radiation Therapy
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously

    Reporting group title
    Temozolomide + Radiation Therapy
    Reporting group description
    		 Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally
    Reporting group title
    Nivolumab + Radiation Therapy
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously

    Reporting group title
    Temozolomide + Radiation Therapy
    Reporting group description
    		 Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date.
    End point type
    Primary
    End point timeframe
    up to 3 years
    End point values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Number of subjects analysed
    280
    280
    Units: Months
        median (confidence interval 95%)
    13.40 (12.62 to 14.29)
    14.88 (13.27 to 16.13)
    Statistical analysis title
    		 Nivolumab over Temozolomide
    Comparison groups
    Temozolomide + Radiation Therapy v Nivolumab + Radiation Therapy
    Number of subjects included in analysis
    560
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0037
    Method
    		 Log-rank test stratified
    Parameter type
    		 Stratified Cox proportional hazard model
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.58
    Notes
    [1] - Hazard Ratio is Nivolumab over Temozolomide

    Secondary: Kaplan-Meier Plot of Progression Free Survival

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    End point title
    		 Kaplan-Meier Plot of Progression Free Survival
    End point description
    PFS was defined as the time from randomization to the date of the first documented tumor progression or death due to any cause. Participants who did not have disease progression or who did not die were censored at the date of last tumor assessment. Participants who did not have any on study tumor assessment and did not have tumor progression or die were censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported progression were censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. Participants who had surgical resection post start of study treatment were censored at the last tumor assessment date prior to initiation of surgical resection. PFS was determined by investigator reported response based on the Radiologic Assessment in Neuro-Oncology criteria.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years)
    End point values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Number of subjects analysed
    280
    280
    Units: Months
        median (confidence interval 95%)
    6.01 (5.65 to 6.21)
    6.21 (5.98 to 6.90)
    Statistical analysis title
    		 Nivolumab over Temozolomide
    Comparison groups
    Nivolumab + Radiation Therapy v Temozolomide + Radiation Therapy
    Number of subjects included in analysis
    560
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    		 Log-rank test stratified
    Parameter type
    		 Stratified Cox proportional hazard model
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.71
    Notes
    [2] - Hazard Ratio is Nivolumab over Temozolomide

    Secondary: Overall Survival Rate at 24 Months

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    End point title
    		 Overall Survival Rate at 24 Months
    End point description
    The overall survival (OS) rate of (nivolumab + radiation therapy) and (temozolomide + radiation therapy) estimated as Kaplan-Meier probability of survival at 24 months. OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date.
    End point type
    Secondary
    End point timeframe
    At 24 Months
    End point values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Number of subjects analysed
    280
    280
    Units: Percentage of participants
        number (confidence interval 95%)
    10.6 (7.3 to 14.6)
    21.2 (16.5 to 26.3)
    No statistical analyses for this end point

    Secondary: Overall Survival in Tumor Mutational Burden (TMB) High Population

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    End point title
    		 Overall Survival in Tumor Mutational Burden (TMB) High Population
    End point description
    OS in all randomized participants that are tumor mutational burden high. OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death due to any cause (up to approximately 6 years)
    End point values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [3] - Data was not and will never be collected
    [4] - Data was not and will never be collected
    No statistical analyses for this end point

    Secondary: Progression Free Survival in Tumor Mutational Burden (TMB) High Population

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    End point title
    		 Progression Free Survival in Tumor Mutational Burden (TMB) High Population
    End point description
    PFS in all randomized participants that are tumor mutational burden high. PFS was defined as the time from randomization to the date of the first documented tumor progression or death due to any cause. Participants who did not have disease progression or who did not die were censored at the date of last tumor assessment. Participants who did not have any on study tumor assessment and did not have tumor progression or die were censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported progression were censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. Participants who had surgical resection post start of study treatment were censored at the last tumor assessment date prior to initiation of surgical resection. PFS was determined by investigator reported response based on the Radiologic Assessment in Neuro-Oncology criteria.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 6 years)
    End point values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - Data was not and will never be collected
    [6] - Data was not and will never be collected
    No statistical analyses for this end point

    Post-hoc: Kaplan-Meier Plot of Overall Survival (OS) - Extended Collection

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    End point title
    		 Kaplan-Meier Plot of Overall Survival (OS) - Extended Collection
    End point description
    OS was defined as the time between the date of randomization and the date of death due to any cause. A participant who has not died was censored at the last known alive date. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date (assessments were made until March 4, 2022).
    End point type
    Post-hoc
    End point timeframe
    From randomization to the date of death due to any cause (up to approximately 6 years)
    End point values
    		 Nivolumab + Radiation Therapy Temozolomide + Radiation Therapy
    Number of subjects analysed
    280
    280
    Units: Months
        median (confidence interval 95%)
    13.34 (12.55 to 14.16)
    14.92 (13.27 to 16.10)
    Statistical analysis title
    		 Nivolumab over Temozolomide
    Comparison groups
    Nivolumab + Radiation Therapy v Temozolomide + Radiation Therapy
    Number of subjects included in analysis
    560
    Analysis specification
    Post-hoc
    Analysis type
    		 [7]
    P-value
    		 = 0.0024
    Method
    		 Log-rank test stratified
    Parameter type
    		 Stratified Cox proportional hazard model
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.55
    Notes
    [7] - Hazard Ratio is Nivolumab over Temozolomide

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs assessed from first dose to 100 days after last dose (up to 67 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Temozolomide + Radiation Therapy
    Reporting group description
    		 Temozolomide 75 mg/m2 daily during radiation therapy, then 150 mg/m2 Days 1-5 for Cycle 1, then increased to 200 mg/m2 Days 1-5 for Cycles 2-6 administered orally

    Reporting group title
    Nivolumab + Radiation Therapy
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks for 8 doses, then 480 mg every 4 weeks administered intravenously

    Serious adverse events
    		 Temozolomide + Radiation Therapy Nivolumab + Radiation Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    141 / 275 (51.27%)
    206 / 278 (74.10%)
         number of deaths (all causes)
    253
    269
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Glioblastoma
         subjects affected / exposed
    0 / 275 (0.00%)
    6 / 278 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Glioblastoma multiforme
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    57 / 275 (20.73%)
    89 / 278 (32.01%)
         occurrences causally related to treatment / all
    0 / 59
    1 / 93
         deaths causally related to treatment / all
    0 / 36
    0 / 41
    Metastases to meninges
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Recurrent cancer
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    3 / 275 (1.09%)
    6 / 278 (2.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour flare
         subjects affected / exposed
    0 / 275 (0.00%)
    15 / 278 (5.40%)
         occurrences causally related to treatment / all
    0 / 0
    16 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour pseudoprogression
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    5 / 275 (1.82%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 275 (0.73%)
    6 / 278 (2.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    2 / 275 (0.73%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Euthanasia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse event
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 275 (1.09%)
    6 / 278 (2.16%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Impaired healing
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 275 (0.00%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Polyserositis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pyrexia
         subjects affected / exposed
    2 / 275 (0.73%)
    7 / 278 (2.52%)
         occurrences causally related to treatment / all
    0 / 2
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular disorder
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    10 / 275 (3.64%)
    7 / 278 (2.52%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anxiety
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apathy
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         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
    4 / 275 (1.45%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Drug dependence
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood altered
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 275 (0.00%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    4 / 275 (1.45%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transaminases increased
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         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
    Compression fracture
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 275 (0.36%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomeningocele
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (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
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    2 / 275 (0.73%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    8 / 275 (2.91%)
    6 / 278 (2.16%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ataxia
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aphasia
         subjects affected / exposed
    3 / 275 (1.09%)
    4 / 278 (1.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebellar stroke
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 275 (0.36%)
    4 / 278 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    11 / 275 (4.00%)
    9 / 278 (3.24%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    5 / 275 (1.82%)
    11 / 278 (3.96%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 275 (0.73%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemianopia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    6 / 275 (2.18%)
    9 / 278 (3.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve disorder
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    3 / 275 (1.09%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorder
         subjects affected / exposed
    2 / 275 (0.73%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         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
    1 / 275 (0.36%)
    4 / 278 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    30 / 275 (10.91%)
    37 / 278 (13.31%)
         occurrences causally related to treatment / all
    0 / 38
    3 / 42
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Subdural hygroma
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 275 (0.73%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 275 (2.91%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 275 (0.73%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 275 (0.36%)
    5 / 278 (1.80%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 275 (1.45%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 275 (0.73%)
    5 / 278 (1.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 275 (0.00%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 275 (0.36%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 275 (0.73%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         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
    Fistula
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         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
    4 / 275 (1.45%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         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
    1 / 275 (0.36%)
    0 / 278 (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
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 275 (0.73%)
    6 / 278 (2.16%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 275 (0.73%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (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
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 275 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 275 (0.36%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 275 (0.00%)
    3 / 278 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 275 (0.73%)
    5 / 278 (1.80%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 275 (0.36%)
    4 / 278 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Steroid diabetes
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Temozolomide + Radiation Therapy Nivolumab + Radiation Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    259 / 275 (94.18%)
    262 / 278 (94.24%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 275 (4.36%)
    16 / 278 (5.76%)
         occurrences all number
    13
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    27 / 275 (9.82%)
    25 / 278 (8.99%)
         occurrences all number
    33
    30
    Fatigue
         subjects affected / exposed
    128 / 275 (46.55%)
    123 / 278 (44.24%)
         occurrences all number
    155
    137
    Gait disturbance
         subjects affected / exposed
    7 / 275 (2.55%)
    24 / 278 (8.63%)
         occurrences all number
    7
    27
    Malaise
         subjects affected / exposed
    13 / 275 (4.73%)
    14 / 278 (5.04%)
         occurrences all number
    13
    15
    Oedema peripheral
         subjects affected / exposed
    15 / 275 (5.45%)
    17 / 278 (6.12%)
         occurrences all number
    15
    17
    Pyrexia
         subjects affected / exposed
    16 / 275 (5.82%)
    30 / 278 (10.79%)
         occurrences all number
    18
    39
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 275 (4.00%)
    21 / 278 (7.55%)
         occurrences all number
    11
    21
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 275 (3.27%)
    18 / 278 (6.47%)
         occurrences all number
    9
    19
    Confusional state
         subjects affected / exposed
    14 / 275 (5.09%)
    23 / 278 (8.27%)
         occurrences all number
    14
    23
    Depression
         subjects affected / exposed
    12 / 275 (4.36%)
    22 / 278 (7.91%)
         occurrences all number
    12
    23
    Insomnia
         subjects affected / exposed
    18 / 275 (6.55%)
    29 / 278 (10.43%)
         occurrences all number
    20
    30
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    18 / 275 (6.55%)
    3 / 278 (1.08%)
         occurrences all number
    30
    6
    Lymphocyte count decreased
         subjects affected / exposed
    32 / 275 (11.64%)
    15 / 278 (5.40%)
         occurrences all number
    43
    24
    Alanine aminotransferase increased
         subjects affected / exposed
    20 / 275 (7.27%)
    23 / 278 (8.27%)
         occurrences all number
    20
    26
    Platelet count decreased
         subjects affected / exposed
    41 / 275 (14.91%)
    8 / 278 (2.88%)
         occurrences all number
    58
    11
    Weight decreased
         subjects affected / exposed
    20 / 275 (7.27%)
    20 / 278 (7.19%)
         occurrences all number
    20
    21
    White blood cell count decreased
         subjects affected / exposed
    15 / 275 (5.45%)
    6 / 278 (2.16%)
         occurrences all number
    22
    9
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    13 / 275 (4.73%)
    14 / 278 (5.04%)
         occurrences all number
    19
    14
    Radiation skin injury
         subjects affected / exposed
    23 / 275 (8.36%)
    30 / 278 (10.79%)
         occurrences all number
    23
    31
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    20 / 275 (7.27%)
    30 / 278 (10.79%)
         occurrences all number
    23
    35
    Cognitive disorder
         subjects affected / exposed
    12 / 275 (4.36%)
    14 / 278 (5.04%)
         occurrences all number
    13
    14
    Dizziness
         subjects affected / exposed
    19 / 275 (6.91%)
    41 / 278 (14.75%)
         occurrences all number
    19
    49
    Dysgeusia
         subjects affected / exposed
    16 / 275 (5.82%)
    14 / 278 (5.04%)
         occurrences all number
    16
    14
    Headache
         subjects affected / exposed
    96 / 275 (34.91%)
    115 / 278 (41.37%)
         occurrences all number
    121
    157
    Hemiparesis
         subjects affected / exposed
    12 / 275 (4.36%)
    24 / 278 (8.63%)
         occurrences all number
    15
    24
    Somnolence
         subjects affected / exposed
    8 / 275 (2.91%)
    19 / 278 (6.83%)
         occurrences all number
    9
    19
    Seizure
         subjects affected / exposed
    36 / 275 (13.09%)
    35 / 278 (12.59%)
         occurrences all number
    43
    48
    Memory impairment
         subjects affected / exposed
    14 / 275 (5.09%)
    19 / 278 (6.83%)
         occurrences all number
    14
    19
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 275 (4.00%)
    16 / 278 (5.76%)
         occurrences all number
    13
    18
    Neutropenia
         subjects affected / exposed
    16 / 275 (5.82%)
    1 / 278 (0.36%)
         occurrences all number
    22
    1
    Lymphopenia
         subjects affected / exposed
    24 / 275 (8.73%)
    7 / 278 (2.52%)
         occurrences all number
    30
    10
    Thrombocytopenia
         subjects affected / exposed
    26 / 275 (9.45%)
    4 / 278 (1.44%)
         occurrences all number
    41
    4
    Eye disorders
    Vision blurred
         subjects affected / exposed
    4 / 275 (1.45%)
    16 / 278 (5.76%)
         occurrences all number
    4
    17
    Dry eye
         subjects affected / exposed
    3 / 275 (1.09%)
    14 / 278 (5.04%)
         occurrences all number
    3
    14
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 275 (2.55%)
    16 / 278 (5.76%)
         occurrences all number
    7
    16
    Constipation
         subjects affected / exposed
    80 / 275 (29.09%)
    54 / 278 (19.42%)
         occurrences all number
    90
    61
    Diarrhoea
         subjects affected / exposed
    23 / 275 (8.36%)
    44 / 278 (15.83%)
         occurrences all number
    32
    71
    Nausea
         subjects affected / exposed
    105 / 275 (38.18%)
    66 / 278 (23.74%)
         occurrences all number
    142
    85
    Vomiting
         subjects affected / exposed
    63 / 275 (22.91%)
    35 / 278 (12.59%)
         occurrences all number
    74
    44
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    88 / 275 (32.00%)
    73 / 278 (26.26%)
         occurrences all number
    89
    73
    Rash
         subjects affected / exposed
    18 / 275 (6.55%)
    40 / 278 (14.39%)
         occurrences all number
    20
    43
    Pruritus
         subjects affected / exposed
    22 / 275 (8.00%)
    31 / 278 (11.15%)
         occurrences all number
    23
    36
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 275 (0.73%)
    18 / 278 (6.47%)
         occurrences all number
    2
    19
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 275 (4.73%)
    25 / 278 (8.99%)
         occurrences all number
    14
    29
    Back pain
         subjects affected / exposed
    17 / 275 (6.18%)
    17 / 278 (6.12%)
         occurrences all number
    18
    18
    Muscular weakness
         subjects affected / exposed
    12 / 275 (4.36%)
    15 / 278 (5.40%)
         occurrences all number
    12
    16
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 275 (4.73%)
    21 / 278 (7.55%)
         occurrences all number
    15
    23
    Urinary tract infection
         subjects affected / exposed
    14 / 275 (5.09%)
    23 / 278 (8.27%)
         occurrences all number
    14
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    50 / 275 (18.18%)
    33 / 278 (11.87%)
         occurrences all number
    60
    36
    Hyperglycaemia
         subjects affected / exposed
    9 / 275 (3.27%)
    15 / 278 (5.40%)
         occurrences all number
    13
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2016
    Added exclusion for subjects with prior hypersensitivity to dacarbazine (DTIC); Added definition of Suspected, Unexpected Serious Adverse Event Reaction (SUSAR) and statement of SUSAR reporting responsibilities.
    24 Feb 2016
    Corrected the temozolomide dose modification guidance during maintenance temozolomide dosing; modified nivolumab dose delay and discontinuation criteria.
    04 May 2016
    Modify cutoff values used to define complete vs partial resection for purposes of randomization. Remove the requirement to perform NANO evaluation prior to discussing MRI results. Replace RANO table for evaluation of response with table for evaluation of progression, applicable to the secondary endpoint of PFS.
    15 Nov 2017
    Removal of the interim analysis for superiority of the primary endpoint of OS. Addition of a secondary endpoint that evaluates, in newly diagnosed, unmethylated O-6-methylguanine DNA methyltransferase glioblastoma, any relationship between OS or PFS and tumor mutational burden in the radiation therapy (RT) + nivolumab arm compared to the RT + TMZ control arm.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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