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    Clinical Trial Results:
    A single stage phase II, multi-centre, open label study of Glivec® in combination with Pioglitazone, Etoricoxib,Dexamethasone and low-dose Treosulfane for anti-inflammatoryand angiostatic treatment in patients with hormone-refractory prostate cancer Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2006-000218-19
    Trial protocol
    		 DE  
    Global end of trial date
    12 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2018
    First version publication date
    15 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSTI571BDE59
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00427999
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clincal Disclosure Office, Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    12 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To investigate the effect of a treatment with Imatinib mesylate (Glivec®), Pioglitazone (Actos®), Etoricoxib (Arcoxia®), and Dexamethasone (Fortecortin®) in combination with metronomic chemotherapy (Treosulfane: Ovastat®) on the PSA response rate in patients with hormone refractory prostate cancer.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Feb 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 67
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    21
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In 11 centers 72 patients were screened, 67 enrolled, of which 65 were treated and 33 completed the treatment phase. Intent to Treat (ITT) population included 61 patients. For the extension follow-up phase 19 patients were included in the safety analysis.

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

    Arms
    Arm title
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Arm description
    		 STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    imatinib
    Investigational medicinal product code
    STI571
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    imatinib 400 mg tablet orally daily

    Investigational medicinal product name
    pioglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    pioglitazone 60 mg tablet orally daily

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    dexamethasone 1 mg tablet orally daily

    Investigational medicinal product name
    etoricoxib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    etoricoxib 60mg tablet orally daily

    Investigational medicinal product name
    Treosulfane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treosulfane 2x 250mg capsules orally daily

    Number of subjects in period 1 [1]
    		STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Started
    65
    Intent to Treat (ITT)
    61
    Extension Follow-up
    19 [2]
    Completed
    33
    Not completed
    32
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    9
         Adverse event, non-fatal
    6
         Unsatisfactory therapeutic effect
    13
         Abnormal laboratory values
    1
         Protocol deviation
    2
    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: 2 patients who were randomized were not treated
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 33 patients completed the core...19 of the 33patient entered the extension portion of the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Reporting group description
    		 STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily

    Reporting group values
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane Total
    Number of subjects
    		 65 65
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 21 21
        From 65-84 years
    		 44 44
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67 ( 7 ) -
    Gender, Male/Female
    Units: participants
        Male
    		 65 65
        Female
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Reporting group description
    		 STI571 (imatinib) 400mg po daily + pioglitazone 60mg po daily + etoricoxib 60mg po daily + dexamethasone 1mg po daily + treosulfane 500mg po daily

    Primary: To investigate the effect of a treatment with Imatinib mesylate, Pioglitazone , Etoricoxib, and Dexamethasone in combination with metronomic chemotherapy (Treosulfane) on the PSA response rate

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    End point title
    		 To investigate the effect of a treatment with Imatinib mesylate, Pioglitazone , Etoricoxib, and Dexamethasone in combination with metronomic chemotherapy (Treosulfane) on the PSA response rate [1]
    End point description
    To investigate the effect of a treatment with Imatinib mesylate, Pioglitazone , Etoricoxib, and Dexamethasone in combination with metronomic chemotherapy (Treosulfane) on the PSA response rate in patients with hormone refractory prostate cancer. A patient will be defined as a responder if a PSA decline of at least 50%, which must be confirmed by a second PSA value 4 weeks later, is observed. A patient will be defined as a non-responder if PSA has not decreased during treatment. Non-response is defined as a 25% increase over the baseline on-study which is confirmed (equal or more) by a second value 4 weeks apart. The absolute increase must account for > 5 ng/ml. No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    24 weeks in the core phase
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: since this is a single arm trial, only summary analysis were performed and are not amenable to this format of database.
    End point values
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Number of subjects analysed
    61
    Units: number of responders
    number (not applicable)
        PSA responder - No
    38
        PSA responder - Yes
    23
    No statistical analyses for this end point

    Secondary: Time to PSA response

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    End point title
    		 Time to PSA response
    End point description
    Time to PSA response, defined as the time from first administration of study drugs to the first PSA value of a confirmed PSA response. Non-responders will be censored with date of final visit/premature discontinuation for the analysis. Median time to PSA response was not achieved
    End point type
    Secondary
    End point timeframe
    every 4 weeks up to 24 weeks in the core phase
    End point values
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Number of subjects analysed
    61 [2]
    Units: days
        median (confidence interval 95%)
    999 (99 to 9999)
    Notes
    [2] - Median time to PSA response was not achieved
    No statistical analyses for this end point

    Secondary: Time to progression-free survival

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    End point title
    		 Time to progression-free survival
    End point description
    Progression-free survival, defined as the time from first administration of study drugs to the first PSA value of a PSA non-responder. Responders will be censored with date of PSA response for the analysis. The median time to PSA progression free survival was not achieved
    End point type
    Secondary
    End point timeframe
    every 4 week upto 24 weeks in the core phase
    End point values
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Number of subjects analysed
    61 [3]
    Units: days
        median (confidence interval 95%)
    999 (99 to 9999)
    Notes
    [3] - The median time to PSA progression free survival was not achieved
    No statistical analyses for this end point

    Secondary: overall survival rate

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    End point title
    		 overall survival rate
    End point description
    Overall survival (OS) is defined as time from randomization to death from any cause or last date known alive. The median time to overall survival rate was not achieved
    End point type
    Secondary
    End point timeframe
    every 4 weeks up to 24 weeks in the core phase
    End point values
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Number of subjects analysed
    61 [4]
    Units: days
        median (confidence interval 95%)
    999 (99 to 9999)
    Notes
    [4] - The median time to overall survival rate was not achieved
    No statistical analyses for this end point

    Secondary: Quality of life assessed with EORTC-30

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    End point title
    		 Quality of life assessed with EORTC-30
    End point description
    Health-related quality of life was assessed with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-30) questionnaire and was presented descriptively. The EORTC QLQ-C30 is a questionnaire including following sub-scales: global health status, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). Scores are averaged for each scale and transformed to 0-100 scale; higher score indicates better quality of life on global health status and functional scales and worse quality of life on symptom scales and financial difficulty scale.
    End point type
    Secondary
    End point timeframe
    baseline and Final Visit
    End point values
    		 STI571+ pioglitazone+ etoricoxib + dexamethasone + treosulfane
    Number of subjects analysed
    61
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline: financial difficulties (n=49)
    11.6 ( 16.03 )
        Baseline: appetite loss (n=50)
    16 ( 29.54 )
        Baseline: dyspnea (n=49)
    20.4 ( 27.06 )
        Baseline: constipation (n=50)
    14 ( 28.64 )
        Baseline: role functioning (n=50)
    74 ( 28.8 )
        Baseline: insomnia (n=49)
    34 ( 34.35 )
        Baseline: cognitive functioning (n=49)
    87.1 ( 16.41 )
        Baseline: diarrhea (n=50)
    9.3 ( 21.34 )
        Baseline: physical functioning (n=50)
    81.7 ( 17.19 )
        Baseline: pain (n=50)
    32.3 ( 32.89 )
        Baseline: emotional functioning (n=49)
    64.6 ( 21.89 )
        Baseline: social functioning (n=49)
    72.4 ( 26.69 )
        Baseline: fatigue (n=50)
    32.9 ( 26.08 )
        Baseline: global health status (n=49)
    60 ( 18.24 )
        Baseline: nausea & vomiting (n=50)
    26 ( 28.8 )
        Final Visit: financial difficulties (n=42)
    19 ( 28.65 )
        Final Visit: appetite loss (n=43)
    24 ( 33.59 )
        Final Visit: dyspnea (n=43)
    38.8 ( 29.03 )
        Final Visit: constipation (n=43)
    6.2 ( 15.01 )
        Final Visit: role functioning (n=43)
    55.4 ( 31.01 )
        Final Visit: insomnia (n=42)
    31.7 ( 32.05 )
        Final Visit: cognitive functioning (n=43)
    81.8 ( 20.51 )
        Final Visit: diarrhea (n=43)
    13.2 ( 23.16 )
        Final Visit: physical functioning (n=43)
    66.7 ( 25.32 )
        Final Visit: pain (n=43)
    26 ( 30.06 )
        Final Visit: emotional functioning (n=43)
    61.8 ( 28.42 )
        Final Visit: social functioning (n=43)
    64 ( 32.52 )
        Final Visit: fatigue (n=43)
    46 ( 29.05 )
        Final Visit: global health status (n=43)
    51 ( 21.76 )
        Final Visit: nausea & vomiting (n=43)
    44.6 ( 31.01 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until LPLV.
    Adverse event reporting additional description
    Consistent with EudraCT specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator. Only deaths occurring within 28 days of final dose are included.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Glivec + study combination -Core
    Reporting group description
    		 Glivec + study combination -Core

    Reporting group title
    Glivec + study combination -Extension
    Reporting group description
    		 Glivec + study combination -Extension

    Serious adverse events
    		 Glivec + study combination -Core Glivec + study combination -Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 65 (33.85%)
    7 / 19 (36.84%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Diabetic vascular disorder
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
    Asthenia
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug ineffective
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
    Burning sensation
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder obstruction
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder tamponade
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (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
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 19 (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
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Glivec + study combination -Core Glivec + study combination -Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 65 (100.00%)
    19 / 19 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Metastases to bone
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Metastases to central nervous system
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Vascular disorders
    Extravasation blood
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Haemorrhage
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Hypotension
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 19 (0.00%)
         occurrences all number
    7
    0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Lymphoedema
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Peripheral venous disease
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 65 (10.77%)
    1 / 19 (5.26%)
         occurrences all number
    8
    1
    Face oedema
         subjects affected / exposed
    15 / 65 (23.08%)
    4 / 19 (21.05%)
         occurrences all number
    16
    4
    Fatigue
         subjects affected / exposed
    21 / 65 (32.31%)
    9 / 19 (47.37%)
         occurrences all number
    24
    11
    General physical health deterioration
         subjects affected / exposed
    1 / 65 (1.54%)
    3 / 19 (15.79%)
         occurrences all number
    1
    3
    Generalised oedema
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Inflammation
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Influenza like illness
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Malaise
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Necrosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    24 / 65 (36.92%)
    6 / 19 (31.58%)
         occurrences all number
    35
    8
    Oedema peripheral
         subjects affected / exposed
    35 / 65 (53.85%)
    12 / 19 (63.16%)
         occurrences all number
    41
    16
    Pain
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Pyrexia
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    23 / 65 (35.38%)
    8 / 19 (42.11%)
         occurrences all number
    27
    8
    Cough
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 19 (5.26%)
         occurrences all number
    4
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    Insomnia
         subjects affected / exposed
    6 / 65 (9.23%)
    0 / 19 (0.00%)
         occurrences all number
    6
    0
    Sleep disorder
         subjects affected / exposed
    6 / 65 (9.23%)
    3 / 19 (15.79%)
         occurrences all number
    6
    3
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 19 (10.53%)
         occurrences all number
    5
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 65 (10.77%)
    1 / 19 (5.26%)
         occurrences all number
    8
    1
    Blood creatinine increased
         subjects affected / exposed
    9 / 65 (13.85%)
    5 / 19 (26.32%)
         occurrences all number
    12
    7
    Blood fibrinogen increased
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    10 / 65 (15.38%)
    4 / 19 (21.05%)
         occurrences all number
    11
    5
    C-reactive protein increased
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 19 (15.79%)
         occurrences all number
    5
    4
    Haematocrit decreased
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Monocyte count decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Monocyte count increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Occult blood
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Prostatic specific antigen increased
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Protein total decreased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Red blood cell count decreased
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 19 (10.53%)
         occurrences all number
    1
    3
    Reticulocyte count increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    13 / 65 (20.00%)
    3 / 19 (15.79%)
         occurrences all number
    13
    4
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Muscle rupture
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Head injury
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Tachyarrhythmia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 19 (5.26%)
         occurrences all number
    4
    1
    Dizziness
         subjects affected / exposed
    6 / 65 (9.23%)
    0 / 19 (0.00%)
         occurrences all number
    9
    0
    Headache
         subjects affected / exposed
    11 / 65 (16.92%)
    1 / 19 (5.26%)
         occurrences all number
    17
    1
    Dysgeusia
         subjects affected / exposed
    7 / 65 (10.77%)
    1 / 19 (5.26%)
         occurrences all number
    7
    1
    Memory impairment
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Paraesthesia
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Polyneuropathy
         subjects affected / exposed
    7 / 65 (10.77%)
    6 / 19 (31.58%)
         occurrences all number
    8
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 65 (32.31%)
    7 / 19 (36.84%)
         occurrences all number
    25
    9
    Anaemia macrocytic
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    19 / 65 (29.23%)
    7 / 19 (36.84%)
         occurrences all number
    23
    8
    Thrombocytopenia
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    Vertigo
         subjects affected / exposed
    7 / 65 (10.77%)
    3 / 19 (15.79%)
         occurrences all number
    8
    3
    Vertigo positional
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 19 (10.53%)
         occurrences all number
    6
    2
    Lacrimation increased
         subjects affected / exposed
    8 / 65 (12.31%)
    0 / 19 (0.00%)
         occurrences all number
    8
    0
    Visual acuity reduced
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 19 (5.26%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 19 (10.53%)
         occurrences all number
    8
    2
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 19 (10.53%)
         occurrences all number
    5
    5
    Diarrhoea
         subjects affected / exposed
    27 / 65 (41.54%)
    6 / 19 (31.58%)
         occurrences all number
    40
    12
    Gastric polyps
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastric ulcer
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Haemorrhoids
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Hiatus hernia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    28 / 65 (43.08%)
    5 / 19 (26.32%)
         occurrences all number
    37
    9
    Toothache
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    16 / 65 (24.62%)
    3 / 19 (15.79%)
         occurrences all number
    19
    3
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Dry skin
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    3
    Petechiae
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    8 / 65 (12.31%)
    2 / 19 (10.53%)
         occurrences all number
    8
    2
    Hyperhidrosis
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Skin dystrophy
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Skin atrophy
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    7 / 65 (10.77%)
    0 / 19 (0.00%)
         occurrences all number
    8
    0
    Skin ulcer
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Kidney fibrosis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Renal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Pollakiuria
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    11 / 65 (16.92%)
    1 / 19 (5.26%)
         occurrences all number
    13
    1
    Cushingoid
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 19 (15.79%)
         occurrences all number
    4
    3
    Hypogonadism male
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 19 (5.26%)
         occurrences all number
    5
    1
    Back pain
         subjects affected / exposed
    7 / 65 (10.77%)
    4 / 19 (21.05%)
         occurrences all number
    8
    5
    Bone pain
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 19 (10.53%)
         occurrences all number
    8
    2
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Muscle spasms
         subjects affected / exposed
    16 / 65 (24.62%)
    5 / 19 (26.32%)
         occurrences all number
    23
    6
    Muscular weakness
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 19 (10.53%)
         occurrences all number
    1
    3
    Musculoskeletal pain
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Myalgia
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Myopathy
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Osteonecrosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 65 (4.62%)
    5 / 19 (26.32%)
         occurrences all number
    3
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Gingivitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 19 (10.53%)
         occurrences all number
    2
    5
    Influenza
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 65 (10.77%)
    3 / 19 (15.79%)
         occurrences all number
    10
    4
    Otitis media
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    8 / 65 (12.31%)
    5 / 19 (26.32%)
         occurrences all number
    8
    5
    Decreased appetite
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Obesity
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Increased appetite
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Zinc deficiency
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2006
    Amendment 1: specifies an extension study to the existing final CSTI571BDE59- protocol and the follow up for patients entering the extension study. .
    29 May 2008
    Amendment 2: a)Adjusting inclusion criterion for extension phase: after enrollment of 30 patients PSA responders were reported by the investigators. Inclusion criteria of extension phase should be adapted in that way, which allows offering study continuation to patients showing at least 30% PSA decrease and no signs for disease progression b)Clarification of efficacy assessment of the extension study c)Clarification of exclusion criteria of the core study-patients with symptomatic CHF according to NYHA classes II-IV are not allowed to enter the trial.Prior therapy with isotopes is not allowed. This includes each radiopharmaceutical licensed for palliation in prostate cancer or painful osseous metastatic disease, like phosphorus (32P),strontium (89SrCl), rhenium (186Re)or samarium (153Sm).Use of any oral anticoagulant is not allowed in this trial d)Clarification of study population, inclusion and exclusion criteria regarding status of hormone refractory prostate cancer-patients with a histologically proven prostate cancer which have entered the hormone refractory state are enrolled into the trial. e)Clarification of Glivec® dosing for dose escalation-dose is increased if PSA increases by at least 5% and this increase is confirmed 4 weeks later. The dose will be increased to 400mg twice daily f)Correction of dosing description for Arcoxia® (etoricoxib) and Fortecortin®(dexamethasone)-Arcoxia is provided as 30 mg tablet; 60 mg daily in the evening. In case of dose reduction 30 mg daily or 60 mg every other day are accepted. Fortecortin is provided as a tablet of 0.5 mg dose strength 1 mg daily is taken at noon g)Clarification of dose adjustments of Arcoxia® (etoricoxib) and Actos® (pioglitazon)- dose adjustment of Arcoxia and Actos coding according to “cardiac general- other” or weight gain what ever comes first should be used g)Timelines were adjusted to the enrollment rate.
    28 Oct 2008
    Amendment 3: a)Adjusting inclusion and exclusion criteria-According to the cited guidelines of EAU some intervals given in the protocol have to be aligned.First, during initial fixing of nadir and reference values regarding PSA level the period between PSA measurements will be adapted to accordant guidelines. Second, the time frame concerning change of androgen deprivation therapy in exclusion criteria will be adequately modified.In compliance with the definition of HRPC inclusion criteria are adjusted. b)Rephrasing the definition of PSA progression-definition of PSA progression was adapted to published PSA response criteria for HRPC (Bubley, J Clin Oncol 1999, 17:3461-67) and the already existing section describing the study variable. C)Changes in drug formulation-Since the indicated dose of 30mg Arcoxia is not available, the dose of 60mg is provided within the study. Given that patients had to take two tablets of 30mg Arcoxia once a day no changes in dose occur. d)Changes of statistical methods (sample size calculation, definition ofresponder/ non-responder)Classification of responder and non-responder was adapted to published recommendations on reporting trial outcomes. e)Correction of minor inconsistencies.
    27 Nov 2009
    Amendment 3: a)Adjusting inclusion and exclusion criteria-According to the cited guidelines of EAU some intervals given in the protocol have to be aligned.First, during initial fixing of nadir and reference values regarding PSA level the period between PSA measurements will be adapted to accordant guidelines. Second, the time frame concerning change of androgen deprivation therapy in exclusion criteria will be adequately modified.In compliance with the definition of HRPC inclusion criteria are adjusted. b)Rephrasing the definition of PSA progression-definition of PSA progression was adapted to published PSA response criteria for HRPC (Bubley, J Clin Oncol 1999, 17:3461-67) and the already existing section describing the study variable. C)Changes in drug formulation-Since the indicated dose of 30mg Arcoxia is not available, the dose of 60mg is provided within the study. Given that patients had to take two tablets of 30mg Arcoxia once a day no changes in dose occur. d)Changes of statistical methods (sample size calculation, definition ofresponder/ non-responder)Classification of responder and non-responder was adapted to published recommendations on reporting trial outcomes. e)Correction of minor inconsistencies.
    29 Jul 2011
    Amendment 5: New data from a retrospective cohort study carried out in France appeared to indicate a increased risk of bladder cancer with pioglitazone-containing medicines. Therefore the EMA’s committee for Medicinal Products for Human Use (CHMP) started a European review of pioglitazone-containing medicines in March 2011 to investigate the signal of a possible increased risk of bladder cancer with pioglitazone. Finalizing its review on antidiabetic pioglitazone-containing medicines and the occurrence of bladder cancer July 2011, the EMA stated in a press release (21th of July) that new contra-indications and warnings for pioglitazone are recommended to reduce the small increased risk of bladder cancer. The benefit-risk balance remains positive in a limited population of type 2 diabetics. In the patient population of the study CSTI571BDE59 this risk could be reduced by including new contraindications and warnings in the protocol and periodic review of the efficacy and safety of the patient’s treatment. Therefore, patients with bladder cancer or bladder cancer in their medical history, macrohematuria of unknown origin and patients with risk factors for bladder cancer (such as exposure to aromatic amines or heavy tobacco smokers) will be excluded from the trial. In light of age-related risks, the balance of benefit and risks should be carefully considered during treatment in the elderly. Furthermore, the treatment of patients on pioglitazone should be reviewed after three to six months (and regularly afterwards) to ensure that only patients who are deriving sufficient benefit continue to take it. Recruitment of this study is finished. Currently, two patients are still under treatment in the extension phase of the study.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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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