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    Clinical Trial Results:
    Primary chemotherapy with temozolomide vs. radiotherapy in patients with low grade gliomas after stratification for genetic 1p loss: a phase III study

    Summary
    EudraCT number
    		 2004-002714-11
    Trial protocol
    		 AT   DE   GB   IT   DK   BE   ES   PT   HU   SE   GR  
    Global end of trial date
    14 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EORTC 22033-26033
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00182819
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    Scientific contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    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
    07 Aug 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Aug 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A randomized study to demonstrate a difference in progression-free survival for primary treatment with temozolomide versus primary irradiation (primary objective).
    Protection of trial subjects
    The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice. The protocol will be approved by the Local, Regional or National Ethics Committees.
    Background therapy
    		 NO background therapy.
    Evidence for comparator
    		 Based on the 3 randomized radiotherapy trials for patients harbouring a low-grade glioma mentioned above there seems to be no survival advantage for immediate radiotherapy or radiation doses above 45 - 50 Gy. Additionally, radiotherapy carries the risk of side effects on cognition. Survival appears to depend mainly on age, grading, histology and neurologic function. Based on the data of the two randomized EORTC trials a group of patients with an inferior prognosis who need immediate therapy can be identified. Therefore a study is proposed for patients carrying prognostic factors for a worse outcome as identified by the previous randomized studies. In this study patients for whom treatment with radiotherapy is commonly prescribed will be randomized between radiotherapy versus chemotherapy with temozolomide. Temozolomide has been demonstrated to have an activity in low-grade glioma. In particular, several studies have shown a higher chemosensitivity for tumors with loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). The latter is especially true for oligodendrogliomas. For this reason, we propose randomization only after genetic testing and stratification for LOH on 1p. The study will investigate if the use of temozolomide improves the time to progression as compared to radiotherapy. Late toxicity, quality of life and cognitive function are important secondary endpoints.
    Actual start date of recruitment
    23 Sep 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 15 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Luxembourg: 1
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 27
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    France: 134
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 49
    Country: Number of subjects enrolled
    Australia: 62
    Country: Number of subjects enrolled
    Canada: 82
    Country: Number of subjects enrolled
    Egypt: 8
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Switzerland: 39
    Country: Number of subjects enrolled
    Netherlands: 113
    Worldwide total number of subjects
    707
    EEA total number of subjects
    492
    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)
    686
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Registration period from 23/09/2005 and 26/03/2010. 78 institutions in 19 countries.

    Pre-assignment
    Screening details
    		 Histologically proven low grade diffuse glioma and after screening: Results of genetic testing (1p) available Patients requiring treatment by at least one of the following: 1. Age ≥40 years 2. Radiologically proven progressive lesion 3. Neurological symptoms others than seizures only 4. Intractable seizures

    Pre-assignment period milestones
    Number of subjects started
    		 707
    Number of subjects completed
    		 477

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 50
    Reason: Number of subjects
    		 Patient lost to follow-up: 6
    Reason: Number of subjects
    		 Patient potentially randomizable: 51
    Reason: Number of subjects
    		 Death not due to progression: 1
    Reason: Number of subjects
    		 Higher grade transformation: 47
    Reason: Number of subjects
    		 Progression or death due to progression: 2
    Reason: Number of subjects
    		 Other / missing: 73
    Period 1
    Period 1 title
    Randomization (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Radiotherapy (RT)
    Arm description
    		 Treatment should start within 6 weeks of randomization. Radiotherapy will consist of a conventionally fractionated regimen, delivering a total dose of 50.4Gy, once daily 1.8 Gy per fraction, 5 days per week, for a total of 28 fractions.
    Arm type
    		 Radiotherapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Temozolomide (TMZ)
    Arm description
    		 Treatment should start within 6 weeks of randomization. Treatment with temozolomide will be continued until disease progression but no longer than 12 treatment cycles (approx. 1 year).
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEMOZOLOMIDE
    Investigational medicinal product code
    Other name
    Temodal
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide will be administered continuously at a daily dose of 75 mg/m2 daily x 21 days, q 28 days. The drug will be administered orally once a day. The dose administered will be determined using the body surface area (BSA) calculated at the beginning of the treatment. The BSA will be calculated from the height and weight obtained at the pretreatment visit.

    Number of subjects in period 1 [1]
    		Radiotherapy (RT) Temozolomide (TMZ)
    Started
    240
    237
    Completed
    199
    200
    Not completed
    41
    37
         treatment never started, ...
    -
    4
         information not available, treatment never started
    18
    -
         Protocol deviation
    23
    33
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 707 patients were registered but only 477 patients were eligible for randomization. Results are presented for randomized patients only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radiotherapy (RT)
    Reporting group description
    		 Treatment should start within 6 weeks of randomization. Radiotherapy will consist of a conventionally fractionated regimen, delivering a total dose of 50.4Gy, once daily 1.8 Gy per fraction, 5 days per week, for a total of 28 fractions.

    Reporting group title
    Temozolomide (TMZ)
    Reporting group description
    		 Treatment should start within 6 weeks of randomization. Treatment with temozolomide will be continued until disease progression but no longer than 12 treatment cycles (approx. 1 year).

    Reporting group values
    		 Radiotherapy (RT) Temozolomide (TMZ) Total
    Number of subjects
    		 240 237 477
    Age categorical
    Units: Subjects
        <40
    		 92 85 177
        >=40
    		 148 152 300
    Age continuous
    Units: years
        median (full range (min-max))
    		 43.5 (18.4 to 71.8) 45 (19.1 to 74.5) -
    Gender categorical
    Units: Subjects
        Female
    		 102 100 202
        Male
    		 138 137 275
    Type of histologically proven low grade
    Units: Subjects
        astrocytoma who grade II
    		 88 79 167
        oligoastrocytoma who grade II
    		 58 60 118
        oligodendroglioma who grade II
    		 94 98 192
    Molecular testing
    Patients having had previous 1p testing in a different laboratory than the one specified for this study had a repeated testing in the central reference laboratory
    Units: Subjects
        1p deleted
    		 98 97 195
        1p normal
    		 107 106 213
        Undeterminable
    		 35 34 69
    MRI contrast enhancement
    Units: Subjects
        No
    		 119 119 238
        Yes
    		 121 118 239
    WHO performance status
    Units: Subjects
        WHO 0
    		 151 143 294
        WHO 1
    		 79 86 165
        WHO 2
    		 10 8 18

    End points

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    End points reporting groups
    Reporting group title
    Radiotherapy (RT)
    Reporting group description
    		 Treatment should start within 6 weeks of randomization. Radiotherapy will consist of a conventionally fractionated regimen, delivering a total dose of 50.4Gy, once daily 1.8 Gy per fraction, 5 days per week, for a total of 28 fractions.

    Reporting group title
    Temozolomide (TMZ)
    Reporting group description
    		 Treatment should start within 6 weeks of randomization. Treatment with temozolomide will be continued until disease progression but no longer than 12 treatment cycles (approx. 1 year).

    Primary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Defining disease progression as radiological or clinical/neurological progression which ever occurs first, PFS is the time interval between the date of randomization and the date of disease progression or death, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow up examination. The patient should consistently be followed with the same diagnostic imaging throughout the study.
    End point type
    Primary
    End point timeframe
    The first follow-up (FU) will be performed 3 months after the start of therapy, then at 3-monthly intervals until progression
    End point values
    		 Radiotherapy (RT) Temozolomide (TMZ)
    Number of subjects analysed
    240
    237
    Units: Years
        median (confidence interval 95%)
    3.82 (3.32 to 4.59)
    3.24 (2.81 to 3.62)
    Statistical analysis title
    		 PFS: TMZ versus RT in ITT
    Statistical analysis description
    Comparison of PFS between both arms (Temozolomide versus Radiotherapy) in intent-to-treat population (all randomized patients according to the allocated treatment)
    Comparison groups
    Radiotherapy (RT) v Temozolomide (TMZ)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.221
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.48

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The duration of survival is the time interval between the date of randomization and the date of death. Patients who were still alive when last traced are censored at the date of last follow up.
    End point type
    Secondary
    End point timeframe
    The first follow-up (FU) will be performed 3 months after the start of therapy, then at 3-monthly intervals until progression. After disease progression Patients are followed every 6 months for survival.
    End point values
    		 Radiotherapy (RT) Temozolomide (TMZ)
    Number of subjects analysed
    240 [1]
    237 [2]
    Units: Years
        median (confidence interval 95%)
    7 (7 to 7)
    7 (7 to 7)
    Notes
    [1] - Median was not reached
    [2] - Median was not reached
    Statistical analysis title
    		 OS: TMZ versus RT in ITT
    Statistical analysis description
    Comparison of OS between both arms (Temozolomide versus Radiotherapy) in intent-to-treat population (all randomized patients according to the allocated treatment)
    Comparison groups
    Radiotherapy (RT) v Temozolomide (TMZ)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 6 weeks of randomization, the first follow-up (FU) will be performed 3 months after treatment start, then at 3-monthly intervals until progression. *Additional evaluations for patients receiving TMZ: Prior to day 1 of each cycle of TMZ
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (xx% AEs are reported as "other" and are not reported as not available from the list of SOC). AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, therefore all AEs (any grade) will be reported in non-SAE section.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Only patients randomized in radiotherapy arm and who started radiotherapy are included in the population

    Reporting group title
    Temozolomide
    Reporting group description
    		 Only patients randomized in Temozolomide arm and who started Temozolomide are included in the population

    Serious adverse events
    		 Radiotherapy Temozolomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 228 (4.82%)
    34 / 235 (14.47%)
         number of deaths (all causes)
    57
    55
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colon cancer
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma stage III
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mucosal inflammation
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         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
    Cough
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    CD4 lymphocytes decreased
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complex partial seizures
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    7 / 235 (2.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Lymphopenia
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    4 / 235 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary incontinence
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         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
    Pain in extremity
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (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
    Bronchitis
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Radiotherapy Temozolomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    200 / 228 (87.72%)
    223 / 235 (94.89%)
    Vascular disorders
    VASCULAR
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    4 / 228 (1.75%)
    2 / 235 (0.85%)
         occurrences all number
    5
    2
    Surgical and medical procedures
    SURGERY/INTRA-OPERATIVE INJURY
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 235 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    CONSTITUTIONAL SYMPTOMS
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    149 / 228 (65.35%)
    175 / 235 (74.47%)
         occurrences all number
    186
    253
    PAIN
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    113 / 228 (49.56%)
    128 / 235 (54.47%)
         occurrences all number
    180
    267
    Immune system disorders
    ALLERGY/IMMUNOLOGY
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    3 / 228 (1.32%)
    12 / 235 (5.11%)
         occurrences all number
    3
    12
    Reproductive system and breast disorders
    SEXUAL/REPRODUCTIVE FUNCTION
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    7 / 228 (3.07%)
    15 / 235 (6.38%)
         occurrences all number
    9
    17
    Respiratory, thoracic and mediastinal disorders
    PULMONARY/UPPER RESPIRATORY
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    15 / 228 (6.58%)
    43 / 235 (18.30%)
         occurrences all number
    17
    54
    Cardiac disorders
    CARDIAC(GENERAL)
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    10 / 228 (4.39%)
    14 / 235 (5.96%)
         occurrences all number
    10
    14
    Nervous system disorders
    NEUROLOGY
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    162 / 228 (71.05%)
    167 / 235 (71.06%)
         occurrences all number
    493
    532
    Blood and lymphatic system disorders
    ANEMIA
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    7 / 228 (3.07%)
    60 / 235 (25.53%)
         occurrences all number
    7
    60
    LEUKOPENIA
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    12 / 228 (5.26%)
    134 / 235 (57.02%)
         occurrences all number
    12
    134
    LYMPHATICS
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    2 / 228 (0.88%)
    9 / 235 (3.83%)
         occurrences all number
    2
    10
    NEUTROPENIA
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    7 / 228 (3.07%)
    90 / 235 (38.30%)
         occurrences all number
    7
    90
    THROMBOCYTOPENIA
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    0 / 228 (0.00%)
    19 / 235 (8.09%)
         occurrences all number
    0
    19
    Ear and labyrinth disorders
    AUDITORY/EAR
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    41 / 228 (17.98%)
    36 / 235 (15.32%)
         occurrences all number
    56
    44
    Eye disorders
    OCULAR/VISUAL
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    36 / 228 (15.79%)
    46 / 235 (19.57%)
         occurrences all number
    62
    64
    Gastrointestinal disorders
    GASTROINTESTINAL
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    70 / 228 (30.70%)
    168 / 235 (71.49%)
         occurrences all number
    120
    424
    Hepatobiliary disorders
    HEPATOBILIAR/PANCREAS
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 235 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    DERMATOLOGY/SKIN
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    112 / 228 (49.12%)
    77 / 235 (32.77%)
         occurrences all number
    142
    118
    Renal and urinary disorders
    RENAL/GENITOURINARY
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    6 / 228 (2.63%)
    16 / 235 (6.81%)
         occurrences all number
    6
    19
    Endocrine disorders
    ENDOCRINE
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    9 / 228 (3.95%)
    12 / 235 (5.11%)
         occurrences all number
    9
    15
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL/SOFT TISSUE
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    22 / 228 (9.65%)
    23 / 235 (9.79%)
         occurrences all number
    30
    28
    Infections and infestations
    INFECTION
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    24 / 228 (10.53%)
    73 / 235 (31.06%)
         occurrences all number
    29
    111
    Metabolism and nutrition disorders
    METABOLIC/LABORATORY
    Additional description: No information.
    alternative dictionary used: CTCAE 3.0
         subjects affected / exposed
    4 / 228 (1.75%)
    4 / 235 (1.70%)
         occurrences all number
    5
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2006
    IB update (Dec 2005) + SUSAR reported since December
    22 Jan 2007
    Protocol version 2.0 Substantial changes - the core PIS / informed consent has been amended with toxicity data provided by the company after market exposure with TMZ - Addendum to the patient information sheet / informed consent has been added for the NEW and the ONGOING patients
    04 Jun 2007
    protocol version 2.0 updates to the Patient information sheet & informed consent update of the IB
    21 May 2010
    update in the drug supply chain

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/20378192
    http://www.ncbi.nlm.nih.gov/pubmed/22560713
    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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