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    Clinical Trial Results:
    A Phase I/II Safety and Exploratory Pharmacodynamic Study of Intravenous Temsirolimus (CCI-779) in Pediatric Subjects with Relapsed/Refractory Solid Tumors

    Summary
    EudraCT number
    		 2007-000371-42
    Trial protocol
    		 FR   DE   PL  
    Global end of trial date
    04 Jan 2012

    Results information
    Results version number
    		 v1
    This version publication date
    16 Mar 2016
    First version publication date
    29 Jul 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    3066K1-139
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00106353
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer Inc., Pfizer ClinicalTrials.gov Call Center, 00 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer Inc., Pfizer ClinicalTrials.gov Call Center, 00 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jul 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: Primary Objective - To evaluate the safety of intravenously (IV) temsirolimus given once weekly to children with solid tumors with disease that is recurrent or refractory to standard therapy or for whom standard therapy is not available. Part 2: Primary objective - To obtain preliminary information on the anti-tumor activity of IV temsirolimus in children with relapsed/refractory neuroblastoma, high-grade gliomas, and rhabdomyosarcoma. Anti-tumor activity will be assessed by determining the percentage of subjects exhibiting objective response (Confirmed response [CR] + Partial response [PR]) within 12 weeks.
    Protection of trial subjects
    The study was in compliance with with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jan 2005
    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
    France: 3
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    71
    EEA total number of subjects
    6
    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)
    2
    Children (2-11 years)
    41
    Adolescents (12-17 years)
    16
    Adults (18-64 years)
    12
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted in 7 countries between 26 January 2005 and 4 January 2012.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Temsirolimus 10 mg/m^2: Part 1
    Arm description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 milligram per square meter (mg/m^2) was administered intravenously once weekly.

    Arm title
    		 Temsirolimus 25 mg/m^2: Part 1
    Arm description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m^2 was administered intravenously once weekly.

    Arm title
    		 Temsirolimus 75 mg/m^2: Part 1
    Arm description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 was administered intravenously once weekly.

    Arm title
    		 Temsirolimus 150 mg/m^2: Part 1
    Arm description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    150 mg/m^2 was administered intravenously once weekly.

    Arm title
    		 High-grade Glioma: Part 2
    Arm description
    		 Temsirolimus was administered intravenously to subjects with high-grade glioma over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 was administered intravenously once weekly.

    Arm title
    		 Neuroblastoma: Part 2
    Arm description
    		 Temsirolimus was administered intravenously to subjects with neuroblatoma over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 was administered intravenously once weekly.

    Arm title
    		 Rhabdomyosarcoma: Part 2
    Arm description
    		 Temsirolimus was administered intravenously to subjects with rhabdomyosarcoma over 60 minutes infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    CCI-779
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 was administered intravenously once weekly.

    Number of subjects in period 1
    		Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Started
    4
    5
    3
    7
    17
    19
    16
    Completed
    0
    0
    0
    0
    1
    1
    0
    Not completed
    4
    5
    3
    7
    16
    18
    16
         Entered follow-up phase
    1
    1
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    1
    2
    1
    -
    -
         Physician decision
    -
    -
    -
    -
    -
    1
    -
         Disease progression
    3
    4
    1
    3
    8
    14
    13
         Symptomatic deterioration
    -
    -
    1
    -
    3
    -
    -
         Death
    -
    -
    -
    -
    3
    -
    1
         Adverse event
    -
    -
    -
    1
    -
    2
    1
         Unspecified
    -
    -
    -
    -
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 71 71
    Age categorical
    Units: Subjects
        Greater than or equal to(>=)1 to less than16 years
    		 54 54
        >=16 to less than (<) 18 years
    		 5 5
        >=18 to less than or equal (<=) to 21 years
    		 12 12
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 46 46
    Subject analysis sets

    Subject analysis set title
    Part 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received temsirolimus intravenously once weekly over 60 minutes infusion in dose escalation schemes of 10 mg/m^2, 25 mg/m^2, 75 mg/m^2 and 150 mg/m^2.

    Subject analysis set title
    Part 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with high-grade glioma, neuroblastoma and rhabdomyosarcoma were administered temsirolimus 75 mg/m^2 intravenously once weekly over 60 minutes infusion.

    Subject analysis sets values
    		 Part 1 Part 2
    Number of subjects
    19
    52
    Age categorical
    Units: Subjects
        Greater than or equal to(>=)1 to less than16 years
    12
    42
        >=16 to less than (<) 18 years
    2
    3
        >=18 to less than or equal (<=) to 21 years
    5
    7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    8
    17
        Male
    11
    35

    End points

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    End points reporting groups
    Reporting group title
    Temsirolimus 10 mg/m^2: Part 1
    Reporting group description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.

    Reporting group title
    Temsirolimus 25 mg/m^2: Part 1
    Reporting group description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.

    Reporting group title
    Temsirolimus 75 mg/m^2: Part 1
    Reporting group description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.

    Reporting group title
    Temsirolimus 150 mg/m^2: Part 1
    Reporting group description
    		 Temsirolimus was administered intravenously over 60 minutes infusion.

    Reporting group title
    High-grade Glioma: Part 2
    Reporting group description
    		 Temsirolimus was administered intravenously to subjects with high-grade glioma over 60 minutes infusion.

    Reporting group title
    Neuroblastoma: Part 2
    Reporting group description
    		 Temsirolimus was administered intravenously to subjects with neuroblatoma over 60 minutes infusion.

    Reporting group title
    Rhabdomyosarcoma: Part 2
    Reporting group description
    		 Temsirolimus was administered intravenously to subjects with rhabdomyosarcoma over 60 minutes infusion.

    Subject analysis set title
    Part 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received temsirolimus intravenously once weekly over 60 minutes infusion in dose escalation schemes of 10 mg/m^2, 25 mg/m^2, 75 mg/m^2 and 150 mg/m^2.

    Subject analysis set title
    Part 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with high-grade glioma, neuroblastoma and rhabdomyosarcoma were administered temsirolimus 75 mg/m^2 intravenously once weekly over 60 minutes infusion.

    Primary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 1

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 1 [1] [2]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to End of Treatment (EOT) (within 30 days of last dose)
    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: Only descriptive data was planned to be reported for this outcome.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
        AEs
    4
    5
    3
    7
        SAEs
    2
    2
    2
    3
    No statistical analyses for this end point

    Primary: Number of Subjects With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 1

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    End point title
    		 Number of Subjects With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 1 [3] [4]
    End point description
    TEAEs are events that occurred on or after initial treatment that were absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs that occurred within 30 days of the last administration of study treatment can be attributed to the treatment period. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [3] - 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: Only descriptive data was planned to be reported for this outcome.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    4
    5
    3
    7
    No statistical analyses for this end point

    Primary: Number of Subjects With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 1

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    End point title
    		 Number of Subjects With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 1 [5] [6]
    End point description
    TEAEs are events that occurred on or after initial treatment that were absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs that occurred within 30 days of the last administration of study treatment can be attributed to the treatment period. National Cancer Institute (NCI)-graded Common Toxicity Criteria (CTC) provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided for each adverse event term. Grades range from 0 (none) to 5 (death). Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [5] - 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: Only descriptive data was planned to be reported for this outcome.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    1
    2
    2
    4
    No statistical analyses for this end point

    Primary: Number of Subjects Who Died: Part 1

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    End point title
    		 Number of Subjects Who Died: Part 1 [7] [8]
    End point description
    Deaths were reported from baseline throughout the 30 day period after last study treatment. After the 30 day reporting period, only deaths believed related to study treatment were to be reported (as SAEs). Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [7] - 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: Only descriptive data was planned to be reported for this outcome.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
        Died=Yes
    3
    1
    0
    0
        Died within 30 days of last dose
    2
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Drug Related Serious Adverse Events (SAEs): Part 1

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    End point title
    		 Number of Subjects With Drug Related Serious Adverse Events (SAEs): Part 1 [9] [10]
    End point description
    SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability / incapacity or are a congenital anomaly or birth defect in the offspring of a study subject. Subjects with documented study treatment toxicity were followed weekly until recovering. After the 30 day reporting period, only SAEs believed to be related to study treatment were to be reported. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [9] - 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: Only descriptive data was planned to be reported for this outcome.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events Causing Temporary Stop of Study Treatment: Part 1

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    End point title
    		 Number of Subjects With Adverse Events Causing Temporary Stop of Study Treatment: Part 1 [11] [12]
    End point description
    Temporary interruption of study treatment; may be followed by resumption of study treatment at current dose or dose modification as determined by the investigator and medical monitor. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [11] - 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: Only descriptive data was planned to be reported for this outcome.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    0
    2
    1
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events Causing Dose Reduction of Study Treatment: Part 1

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    End point title
    		 Number of Subjects With Adverse Events Causing Dose Reduction of Study Treatment: Part 1 [13] [14]
    End point description
    Dose reduction for individual subject allowed if a dose limiting toxicity (DLT) occurred; may continue treatment following reduction by 1 to 2 dose levels (determined by investigator and medical monitor). DLT= failure to recover to National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 3.0 grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity within 3 weeks (leading to a treatment delay of >3 weeks) unless investigator and medical monitor agree subject should remain in the study. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [13] - 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: Only descriptive data was planned to be reported for this outcome.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 1

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    End point title
    		 Number of Subjects With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 1 [15] [16]
    End point description
    Number of subjects who met the criteria for PCI changes (based on baseline values before treatment); criteria defined as body temperature greater than (>) 39 degrees Celsius (C), respiratory rate >20 beats per minute (bpm), and systolic and diastolic blood pressure (BP) >200/110 millimeters of mercury (mmHg). Subjects may be reported in more than 1 category. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [15] - 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: Only descriptive data was planned to be reported for this outcome.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
        Temperature >39 degrees C
    1
    2
    1
    3
        Respiratory rate >20 bpm
    4
    5
    3
    7
        Systolic/Diastolic BP >200/110 mmHg
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 1

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    End point title
    		 Number of Subjects With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 1 [17] [18]
    End point description
    Number of subjects who met the PCI criteria (grades 1 through 5) for laboratory values (hematology and serum chemistry). NCI-CTC provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided with grades ranging from 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening or disabling), to 5 (death). Subjects may be reported in more than 1 category. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [17] - 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: Only descriptive data was planned to be reported for this outcome.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    4
    5
    3
    7
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Objective Response (OR) at Week 12: Part 2

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    End point title
    		 Percentage of Subjects With Objective Response (OR) at Week 12: Part 2 [19] [20]
    End point description
    Measured as Complete response (CR), Very good partial response (VGPR), or PR on at least 2 occasions >= 4 weeks apart within first 12 weeks. CR=disappearance of all primary and metastatic lesions; Homovanillic acid, Vanillymandelic acid (HVA/VMA) normal; bone marrow immunocytology negative. VGPR=disappearance of all metastatic lesions (residual areas of uptake on bone permitted); 90 to 99 percent (%) decrease in primary disease measurement; HVA/VMA normal or both decreased >90%. PR=at least 50% decrease in primary and metastatic disease. Number of bone sites decreased by at least 50%. Efficacy evaluable population included all subjects who received at least 3 doses of study treatment.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [19] - 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: Only descriptive data was planned to be reported for this outcome.
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    15 [21]
    15 [22]
    12 [23]
    Units: percentage of subjects
        number (not applicable)
    0
    6.67
    0
    Notes
    [21] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [22] - N= Number of subjects who were evaluable for this measure for each group respectively..
    [23] - N= Number of subjects who were evaluable for this measure for each group respectively.
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Reached Maximum Tolerated Dose Due to Dose Limiting Toxicity: Part 1

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    End point title
    		 Number of Subjects Who Reached Maximum Tolerated Dose Due to Dose Limiting Toxicity: Part 1 [24]
    End point description
    Maximum tolerated dose (MTD) defined as the dose level at which >=2 of 3 subjects or >=2 of 6 subjects if the dose level had been expanded, experienced a dose limiting toxicity (DLT) by day 21 after the first dose of study treatment. DLT defined as failure to recover to NCI-CTCAE version 3.0 grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity within 3 weeks (leading to a treatment delay of > 3 weeks) unless the investigator and the medical monitor agree that the subject should remain in the study. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 6
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: subjects
    0
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Maximum Observed Whole Blood Concentration (Cmax): Part 1

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    End point title
    		 Maximum Observed Whole Blood Concentration (Cmax): Part 1 [25]
    End point description
    Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hours (hrs) post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: nanogram per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 5, 3, 7)
    307 ( 91.3 )
    487 ( 141 )
    480 ( 135 )
    9230 ( 18200 )
        Cycle 2 (n = 4, 4, 3, 5)
    252 ( 98.3 )
    403 ( 128 )
    807 ( 279 )
    2570 ( 1110 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Whole Blood Concentration (Tmax): Part 1

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    End point title
    		 Time to Reach Maximum Observed Whole Blood Concentration (Tmax): Part 1 [26]
    End point description
    Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: hr
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 5, 3, 7)
    1 ( 0.143 )
    1.1 ( 0.074 )
    1.3 ( 0.231 )
    1.1 ( 0.218 )
        Cycle 2 (n = 4, 4, 3, 5)
    1.1 ( 0.236 )
    1.7 ( 0.983 )
    1.2 ( 0.202 )
    1.2 ( 0.212 )
    No statistical analyses for this end point

    Secondary: Half-Life (t1/2): Part 1

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    End point title
    		 Half-Life (t1/2): Part 1 [27]
    End point description
    Plasma decay half-life is the time measured for the whole blood concentration to decrease by one half. Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively. Here 99999 in standard deviation (SD) signifies that data was not estimable. SD was not estimable since only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4 [28]
    4 [29]
    3 [30]
    5 [31]
    Units: hr
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 4, 1, 4)
    10.6 ( 0.556 )
    16.4 ( 6.9 )
    24 ( 99999 )
    19.3 ( 10.5 )
        Cycle 2 (n = 4, 3, 3, 5)
    14.4 ( 4.42 )
    14.3 ( 10.4 )
    25.4 ( 1.83 )
    24.2 ( 7.58 )
    Notes
    [28] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [29] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [30] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [31] - N= Number of subjects who were evaluable for this measure for each group respectively..
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 1

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    End point title
    		 Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 1 [32]
    End point description
    AUC (0-t)= Area under the whole blood concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4
    5
    3
    7
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 5, 3, 7)
    1670 ( 730 )
    3890 ( 3190 )
    3750 ( 2420 )
    9680 ( 12800 )
        Cycle 2 (n = 4, 4, 3, 5)
    1520 ( 583 )
    1930 ( 1090 )
    3420 ( 1230 )
    4850 ( 1810 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve (AUC): Part 1

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    End point title
    		 Area Under the Concentration-Time Curve (AUC): Part 1 [33]
    End point description
    AUC= Area under the concentration versus time curve from time zero (pre-dose) over time. It is used to characterize extent of exposure. Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively. 99999 in standard deviation (SD) signifies that data was not estimable. SD was not estimable since only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4 [34]
    4 [35]
    3 [36]
    5 [37]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 4, 1, 4)
    2000 ( 959 )
    4640 ( 3430 )
    2810 ( 99999 )
    13000 ( 17000 )
        Cycle 2 (n = 4, 3, 3, 5)
    1600 ( 540 )
    2580 ( 768 )
    3500 ( 1140 )
    4960 ( 2000 )
    Notes
    [34] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [35] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [36] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [37] - N= Number of subjects who were evaluable for this measure for each group respectively.
    No statistical analyses for this end point

    Secondary: Clearance (CL): Part 1

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    End point title
    		 Clearance (CL): Part 1 [38]
    End point description
    CL is a hypothetical volume of blood that is cleared of drug in a given unit of time. Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively. Here 99999 in standard deviation (SD) signifies that data was not estimable. SD was not estimable since only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4 [39]
    4 [40]
    3 [41]
    5 [42]
    Units: liter/hr (L/hr)
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 4, 1, 4)
    7.02 ( 3.68 )
    10.4 ( 6.45 )
    38.1 ( 99999 )
    47.9 ( 45.8 )
        Cycle 2 (n = 4, 3, 3, 5)
    8.99 ( 5.27 )
    13.8 ( 9.06 )
    30.6 ( 15.5 )
    39 ( 24.4 )
    Notes
    [39] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [40] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [41] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [42] - N= Number of subjects who were evaluable for this measure for each group respectively.
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss): Part 1

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    End point title
    		 Volume of Distribution at Steady State (Vss): Part 1 [43]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively. 99999 in standard deviation (SD) signifies that data was not estimable. SD was not estimable since only 1 subject was evaluable.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4 [44]
    4 [45]
    3 [46]
    5 [47]
    Units: liter
    arithmetic mean (standard deviation)
        Cycle 1 (n = 4, 4, 1, 4)
    85.2 ( 35 )
    189 ( 44.2 )
    783 ( 99999 )
    512 ( 689 )
        Cycle 2 (n = 4, 3, 3, 5)
    250 ( 290 )
    201 ( 132 )
    601 ( 347 )
    353 ( 130 )
    Notes
    [44] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [45] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [46] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [47] - N= Number of subjects who were evaluable for this measure for each group respectively.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Overall Response: Part 1

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    End point title
    		 Percentage of Subjects With Best Overall Response: Part 1 [48]
    End point description
    Best overall response is the best response recorded from baseline until disease progression or recurrence. Measured as CR, PR, Stable Disease (SD), Progressive Disease (PD), or Unknown. CR=disappearance of all primary and metastatic lesions. PR=at least a 50% decrease in primary disease measurement. SD=no new lesions; decrease of <50% in all lesions with no lesion increasing >25%. PD=any new lesion; at least a 25% increase in any disease measurement (reference smallest disease measurement recorded since start of treatment); or appearance of 1 or more new lesions. Tumor response considered Unknown if assessment prior to Day 37. Safety population included all subjects who received at least 1 dose of study medication. Here, 'n' signifies those subjects who were evaluable for particular cycle for each group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or recurrence (actual greatest response day is up to Day 49)
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 Temsirolimus 10 mg/m^2: Part 1 Temsirolimus 25 mg/m^2: Part 1 Temsirolimus 75 mg/m^2: Part 1 Temsirolimus 150 mg/m^2: Part 1
    Number of subjects analysed
    4 [49]
    4 [50]
    3 [51]
    7 [52]
    Units: percentage of subjects
    number (not applicable)
        Complete response
    1
    0
    0
    0
        Partial response
    0
    0
    0
    0
        Stable disease
    0
    2
    3
    2
        Progressive disease
    3
    2
    0
    3
        Unknown response
    0
    0
    0
    2
    Notes
    [49] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [50] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [51] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [52] - N= Number of subjects who were evaluable for this measure for each group respectively.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Exhibiting Freedom From Progression at Week 12: Part 2

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    End point title
    		 Percentage of Subjects Exhibiting Freedom From Progression at Week 12: Part 2 [53]
    End point description
    Freedom from progression measured as Stable Disease (SD) or better and no Progressive Disease (PD); (CR+VGPR+Mixed Response [MR]+PR+SD). CR=disappearance of all primary and metastatic lesions. VGPR=disappearance of all metastatic lesions. MR=no new lesions; at least 50% decrease in any 1 disease measurement with <50% decrease in any other disease measurement or an increase of <25% in any lesion). SD=no new lesions; decrease of <50% in all lesions with no lesion increasing >25%. PD=at least a 25% increase in any disease measurement; or the appearance of 1 or more new lesions. Efficacy evaluable population included all subjects who received at least 3 doses of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    15 [54]
    15 [55]
    15 [56]
    Units: percentage of subjects
        number (confidence interval 95%)
    46.67 (21.27 to 73.41)
    40 (16.34 to 67.71)
    8.33 (0.21 to 38.48)
    Notes
    [54] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [55] - N= Number of subjects who were evaluable for this measure for each group respectively.
    [56] - N= Number of subjects who were evaluable for this measure for each group respectively.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 [57]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
        AEs
    17
    19
    16
        SAEs
    10
    6
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 2

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    End point title
    		 Number of Subjects With Drug Related Treatment Emergent Adverse Events (TEAEs): Part 2 [58]
    End point description
    Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
    17
    18
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 2

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    End point title
    		 Number of Subjects With Drug Related Grade 3 and Higher Treatment Emergent Adverse Events (TEAEs): Part 2 [59]
    End point description
    Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. NCI-CTC provides descriptive terminology for adverse event reporting. A grading (severity) scale was provided for each adverse event term. Grades range from 0 (none) to 5 (death). Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
    5
    11
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Died: Part 2

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    End point title
    		 Number of Subjects Who Died: Part 2 [60]
    End point description
    Deaths were reported from baseline throughout the 30 day period after last study treatment. After the 30 day reporting period, only deaths believed related to study treatment were to be reported (as SAEs). Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
        Died=Yes
    5
    2
    4
        Died within 30 days of last dose
    3
    0
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Drug Related Serious Adverse Events (SAEs): Part 2

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    End point title
    		 Number of Subjects With Drug Related Serious Adverse Events (SAEs): Part 2 [61]
    End point description
    An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Subjects with documented study treatment toxicity were followed weekly until recovering. After the 30 day reporting period, only SAEs believed to be related to study treatment were to be reported. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
    2
    3
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events Causing Temporary Stop of Study Treatment: Part 2

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    End point title
    		 Number of Subjects With Adverse Events Causing Temporary Stop of Study Treatment: Part 2 [62]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Temporary interruption of study treatment may be followed by resumption of study treatment at current dose or dose modification as determined by the investigator and medical monitor. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
    9
    12
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events Causing Dose Reduction of Study Treatment: Part 2

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    End point title
    		 Number of Subjects With Adverse Events Causing Dose Reduction of Study Treatment: Part 2 [63]
    End point description
    Dose reduction for individual subject allowed if a DLT occurred; may continue treatment following reduction by 1 to 2 dose levels (determined by investigator and medical monitor). DLT= failure to recover to National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 3.0 grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related toxicity within 3 weeks (leading to a treatment delay of >3 weeks) unless investigator and medical monitor agree subject should remain in the study. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
    5
    10
    6
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 2

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    End point title
    		 Number of Subjects With Potentially Clinically Important (PCI) Changes in Vital Signs: Part 2 [64]
    End point description
    Number of subjects who met the criteria for PCI changes (based on baseline values before treatment); criteria defined as body temperature >39 degrees C, respiratory rate >20 bpm, and systolic and diastolic BP >200/110 mmHg. Subjects may be reported in more than 1 category. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
        Temperature >39 degrees C
    0
    0
    0
        Respiratory rate >20 bpm
    16
    18
    14
        Systolic/Diastolic BP >200/110 mmHg
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 2

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    End point title
    		 Number of Subjects With Potentially Clinically Important (PCI) Values by National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade for Laboratory Values: Part 2 [65]
    End point description
    Number of subjects who met the PCI criteria (grades 1 through 5) for laboratory values (hematology and serum chemistry). NCI-CTC provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided with grades ranging from 0 (none), 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening or disabling), to 5 (death). Subjects were reported in more than 1 category. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (within 30 days of last dose)
    Notes
    [65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed in Part 1 and Part 2 separately.
    End point values
    		 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Number of subjects analysed
    17
    19
    16
    Units: subjects
    17
    19
    15
    No statistical analyses for this end point

    Secondary: Maximum Observed Whole Blood Concentration (Cmax): Part 2

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    End point title
    		 Maximum Observed Whole Blood Concentration (Cmax): Part 2
    End point description
    Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    35 [66]
    Units: ng/mL
        arithmetic mean (standard deviation)
    6280 ( 21000 )
    Notes
    [66] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Average Whole Blood Concentration (Cavg): Part 2

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    End point title
    		 Average Whole Blood Concentration (Cavg): Part 2
    End point description
    Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    31 [67]
    Units: ng/mL
        arithmetic mean (standard deviation)
    82.8 ( 143 )
    Notes
    [67] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Whole Blood Concentration (Tmax): Part 2

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    End point title
    		 Time to Reach Maximum Observed Whole Blood Concentration (Tmax): Part 2
    End point description
    Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose),1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    35 [68]
    Units: hours
        median (full range (min-max))
    1 (0 to 6)
    Notes
    [68] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Half-Life (t1/2): Part 2

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    End point title
    		 Half-Life (t1/2): Part 2
    End point description
    Half-life is the time measured for the whole blood concentration to decrease by one half. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    26 [69]
    Units: hours
        arithmetic mean (standard deviation)
    30.65 ( 13.63 )
    Notes
    [69] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 2

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    End point title
    		 Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)]: Part 2
    End point description
    AUC (0-t)= Area under the whole blood concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    35 [70]
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    13100 ( 22700 )
    Notes
    [70] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve at Steady State (AUCss): Part 2

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    End point title
    		 Area Under the Concentration-time Curve at Steady State (AUCss): Part 2
    End point description
    AUCss is the area under the drug concentration in whole blood versus time curve over one dosage interval at steady-state. It is used to characterize extent of exposure. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    31 [71]
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    13900 ( 24100 )
    Notes
    [71] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Clearance (CL): Part 2

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    End point title
    		 Clearance (CL): Part 2
    End point description
    CL is a hypothethical volume of blood that is cleared of drug in a given unit of time. Safety population included all subjects who received at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose),1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 2
    Number of subjects analysed
    31 [72]
    Units: L/hr
        arithmetic mean (standard deviation)
    14.3 ( 14 )
    Notes
    [72] - N= Number of subjects who were evaluable for this measure.
    No statistical analyses for this end point

    Secondary: Concentration in Whole Blood (Cp) and Concentration in Whole Blood at Time Zero (Cp Time 0): Part 1 and Part 2

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    End point title
    		 Concentration in Whole Blood (Cp) and Concentration in Whole Blood at Time Zero (Cp Time 0): Part 1 and Part 2
    End point description
    Pharmacokinetic parameters determined in whole blood; derived from the concentration-versus-time profiles using noncompartmental analysis method. Measured as ng/mL.
    End point type
    Secondary
    End point timeframe
    Part 1: 0 (pre-dose), 1, 2, 6, 24, and 168 hrs post-dose of Cycle 1 and 0 (pre-dose), 1, 2, 6, 24, 72, 96, and 168 hrs post-dose of Cycle 2; Part2: 0 (pre-dose), 1, 6, 24, 48, 72, 96, and 168 hrs post-dose of Cycle 2 (cycles are approximately 21 days)
    End point values
    		 Part 1 Part 2
    Number of subjects analysed
    0 [73]
    0 [74]
    Units: subjects
    Notes
    [73] - Data was not analyzed for this outcome measure.
    [74] - Data was not analyzed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Number of Subjects for Change From Baseline in the Phosphorylation of Mammalian Target of Rapamycin (mTOR) Pathway Proteins: Part 1 and Part 2

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    End point title
    		 Number of Subjects for Change From Baseline in the Phosphorylation of Mammalian Target of Rapamycin (mTOR) Pathway Proteins: Part 1 and Part 2
    End point description
    Optional bone marrow sampling for pharmacodynamic analysis of effects of study treatment. Data may not be collected for a majority of subjects and was not to be summarized if collection was sparse.
    End point type
    Secondary
    End point timeframe
    Part 1:Baseline,1,2,6,24,168 hrs post-dose of Cycle 1;additional 0 (Pre-dose),24,72,96 hrs, Day 16 to 21 of cycle 2, EOT(within 30 days of last dose); Part 2:Baseline,Day16 to 21 in Cycle 2, at time of disease progression, EOT(within 30 days of last dose)
    End point values
    		 Part 1 Part 2
    Number of subjects analysed
    0 [75]
    0 [76]
    Units: subjects
    Notes
    [75] - Data was not analyzed for this outcome measure.
    [76] - Data was not analyzed for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after last dose of study drug
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Temsirolimus 10mg/m2: Part 1
    Reporting group description
    		 Temsirolimus 10 mg/m^2 administered intravenously once weekly over 60 minutes infusion.

    Reporting group title
    Temsirolimus 25mg/m2: Part 1
    Reporting group description
    		 Temsirolimus 25 mg/m^2 administered intravenously once weekly over 60 minutes infusion.

    Reporting group title
    Temsirolimus 75mg/m2: Part 1
    Reporting group description
    		 Temsirolimus 75 mg/m^2 administered intravenously once weekly over 60 minutes infusion.

    Reporting group title
    Temsirolimus 150mg/m2: Part 1
    Reporting group description
    		 Temsirolimus 150 mg/m^2 intravenously administered once weekly over 60 minutes infusion.

    Reporting group title
    High-grade Glioma: Part 2
    Reporting group description
    		 Subjects with high-grade glioma were administered temsirolimus 75 mg/m^2 intravenously once weekly over 60 minutes infusion.

    Reporting group title
    Neuroblastoma: Part 2
    Reporting group description
    		 Subjects with neuroblastoma were administered temsirolimus 75 mg/m^2 intravenously once weekly over 60 minutes infusion.

    Reporting group title
    Rhabdomyosarcoma: Part 2
    Reporting group description
    		 Subjects with rhabdomyosarcoma were administered temsirolimus 75 mg/m^2 intravenously once weekly over 60 minutes infusion.

    Serious adverse events
    		 Temsirolimus 10mg/m2: Part 1 Temsirolimus 25mg/m2: Part 1 Temsirolimus 75mg/m2: Part 1 Temsirolimus 150mg/m2: Part 1 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    10 / 17 (58.82%)
    8 / 19 (42.11%)
    7 / 16 (43.75%)
         number of deaths (all causes)
    2
    0
    0
    0
    3
    0
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rhabdomyosarcoma
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Pain management
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 1
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coordination abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drooling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nail infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Temsirolimus 10mg/m2: Part 1 Temsirolimus 25mg/m2: Part 1 Temsirolimus 75mg/m2: Part 1 Temsirolimus 150mg/m2: Part 1 High-grade Glioma: Part 2 Neuroblastoma: Part 2 Rhabdomyosarcoma: Part 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    17 / 17 (100.00%)
    19 / 19 (100.00%)
    15 / 16 (93.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroblastoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    4
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 19 (5.26%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    4
    1
    2
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    1
    Surgical and medical procedures
    Ear operation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Nail operation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Tooth repair
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    0
    7
    1
    Axillary pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Catheter site rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    1
    Device occlusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Extravasation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    4 / 7 (57.14%)
    6 / 17 (35.29%)
    6 / 19 (31.58%)
    5 / 16 (31.25%)
         occurrences all number
    1
    1
    0
    7
    8
    11
    10
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Injection site bruising
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    1
    2
    4
    0
    3
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    3 / 19 (15.79%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    17
    2
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    1 / 17 (5.88%)
    9 / 19 (47.37%)
    4 / 16 (25.00%)
         occurrences all number
    0
    2
    1
    6
    1
    29
    5
    Swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    2
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Bronchospasm
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    1
    Cough
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    5 / 17 (29.41%)
    6 / 19 (31.58%)
    4 / 16 (25.00%)
         occurrences all number
    3
    2
    1
    3
    8
    26
    7
    Dysphonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    3 / 19 (15.79%)
    4 / 16 (25.00%)
         occurrences all number
    1
    1
    0
    0
    3
    5
    6
    Epistaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    2 / 16 (12.50%)
         occurrences all number
    2
    0
    0
    0
    0
    30
    3
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    3
    Lung infiltration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    4 / 19 (21.05%)
    1 / 16 (6.25%)
         occurrences all number
    3
    0
    0
    0
    0
    8
    2
    Pharyngeal erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    Pneumonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Pneumothorax
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    10
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    3
    1
    9
    3
    Suffocation feeling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Tachypnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 19 (5.26%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    0
    0
    3
    2
    4
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Confusional state
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Irritability
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    2
    0
    Mood altered
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    1 / 7 (14.29%)
    6 / 17 (35.29%)
    7 / 19 (36.84%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    16
    2
    13
    28
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    6 / 19 (31.58%)
    5 / 16 (31.25%)
         occurrences all number
    3
    3
    10
    6
    8
    54
    6
    Blood albumin decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    6
    0
    0
    4
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    4 / 19 (21.05%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    4
    0
    4
    5
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    35
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    6
    0
    1
    1
    0
    Blood calcium increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    6 / 19 (31.58%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    4
    3
    9
    16
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    10
    0
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    0
    Blood glucose decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    4
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 17 (5.88%)
    4 / 19 (21.05%)
    1 / 16 (6.25%)
         occurrences all number
    0
    3
    9
    2
    7
    54
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Blood magnesium increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    4
    0
    1
    0
    0
    15
    2
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    1 / 17 (5.88%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    0
    7
    14
    9
    1
    10
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    4 / 19 (21.05%)
    0 / 16 (0.00%)
         occurrences all number
    0
    4
    9
    0
    0
    19
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Blood pressure decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    8
    0
    Blood sodium increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    4 / 17 (23.53%)
    6 / 19 (31.58%)
    2 / 16 (12.50%)
         occurrences all number
    2
    2
    3
    4
    20
    66
    5
    Blood urea increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    1 / 17 (5.88%)
    6 / 19 (31.58%)
    1 / 16 (6.25%)
         occurrences all number
    5
    0
    13
    6
    2
    60
    1
    High density lipoprotein decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    3 / 3 (100.00%)
    3 / 7 (42.86%)
    2 / 17 (11.76%)
    4 / 19 (21.05%)
    0 / 16 (0.00%)
         occurrences all number
    0
    7
    11
    11
    2
    13
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    4 / 17 (23.53%)
    7 / 19 (36.84%)
    2 / 16 (12.50%)
         occurrences all number
    1
    7
    6
    4
    10
    24
    2
    Weight decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
         occurrences all number
    1
    0
    0
    2
    0
    2
    4
    Weight increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    3 / 3 (100.00%)
    5 / 7 (71.43%)
    2 / 17 (11.76%)
    6 / 19 (31.58%)
    1 / 16 (6.25%)
         occurrences all number
    1
    11
    13
    14
    4
    79
    2
    White blood cell count increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    0
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    9
    0
    Head injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Humerus fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Radiation injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    Sunburn
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    4
    Nervous system disorders
    Accessory nerve disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Ataxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    3
    0
    Dyskinesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    3 / 17 (17.65%)
    4 / 19 (21.05%)
    4 / 16 (25.00%)
         occurrences all number
    0
    7
    2
    5
    4
    12
    10
    Hemiparesis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    4
    Neuropathy peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Partial seizures
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    3
    0
    0
    3
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    4
    0
    Seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Spinal cord compression
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Syncope
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    0 / 17 (0.00%)
    5 / 19 (26.32%)
    3 / 16 (18.75%)
         occurrences all number
    7
    0
    0
    12
    0
    73
    4
    Leukopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    4 / 19 (21.05%)
    5 / 16 (31.25%)
         occurrences all number
    0
    0
    0
    0
    0
    27
    12
    Lymphopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    16
    0
    1
    10
    3
    Neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    0
    1
    0
    79
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    5 / 17 (29.41%)
    6 / 19 (31.58%)
    6 / 16 (37.50%)
         occurrences all number
    7
    0
    1
    12
    11
    37
    16
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    2
    0
    External ear disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    External ear pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Eye disorders
    Exophthalmos
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Eye disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    Eye pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    Lacrimation increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    6 / 19 (31.58%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    16
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Breath odour
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Chapped lips
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 17 (5.88%)
    5 / 19 (26.32%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    3
    1
    7
    0
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    3
    5
    3
    5
    1
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eructation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Glossitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    4 / 7 (57.14%)
    1 / 17 (5.88%)
    4 / 19 (21.05%)
    4 / 16 (25.00%)
         occurrences all number
    0
    1
    4
    7
    2
    12
    4
    Oesophageal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    4
    2
    4
    0
    2
    2
    Oral disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Oral pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    5
    0
    0
    0
    0
    0
    Periodontal disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Rectal discharge
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    5 / 19 (26.32%)
    3 / 16 (18.75%)
         occurrences all number
    1
    1
    0
    1
    2
    7
    12
    Tooth impacted
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    5 / 17 (29.41%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    3
    4
    1
    5
    7
    5
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hepatomegaly
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    3
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    2
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    3 / 19 (15.79%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    1
    0
    1
    6
    3
    Ecchymosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Exfoliative rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nail bed inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Nail bed tenderness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    5
    0
    0
    7
    1
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    5 / 17 (29.41%)
    3 / 19 (15.79%)
    3 / 16 (18.75%)
         occurrences all number
    1
    2
    2
    5
    10
    7
    3
    Rash erythematous
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Rash follicular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Scab
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Glycosuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    1
    Haematuria
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    1
    Haemoglobinuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Micturition disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    8
    1
    Urethral pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    0
    Urinary tract disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Urogenital haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    6 / 19 (31.58%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    2
    2
    12
    4
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 17 (11.76%)
    4 / 19 (21.05%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    7
    2
    6
    5
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Muscle spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    3
    0
    Muscle twitching
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    0
    1
    1
    3
    5
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Pain in extremity
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    5 / 19 (26.32%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    0
    0
    1
    18
    2
    Pain in jaw
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Acne pustular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    0
    Candida infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Catheter site infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    7
    0
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    1
    Cystitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Device related infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    2
    Folliculitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Furuncle
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    Laryngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Lobar pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Lung infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Nail infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    3
    0
    Osteomyelitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Otitis externa
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    7
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    10
    0
    Pharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Pyoderma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    4 / 19 (21.05%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    8
    0
    Shunt infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    6
    0
    Skin candida
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    5 / 19 (26.32%)
    3 / 16 (18.75%)
         occurrences all number
    1
    1
    0
    0
    4
    18
    4
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    6 / 7 (85.71%)
    3 / 17 (17.65%)
    6 / 19 (31.58%)
    6 / 16 (37.50%)
         occurrences all number
    3
    0
    2
    8
    5
    11
    8
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    4
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    2
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    12
    0
    7
    5
    10
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 17 (11.76%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
         occurrences all number
    0
    2
    0
    4
    6
    32
    7
    Hypermagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    2 / 16 (12.50%)
         occurrences all number
    0
    9
    0
    0
    0
    13
    3
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    3 / 16 (18.75%)
         occurrences all number
    1
    0
    1
    11
    0
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    37
    3
    Hypochloraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    29
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    2
    0
    28
    3
    Hypokalaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    1 / 17 (5.88%)
    4 / 19 (21.05%)
    3 / 16 (18.75%)
         occurrences all number
    3
    0
    0
    7
    2
    15
    4
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    6
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    6 / 19 (31.58%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    33
    0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Polydipsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2005
    Protocol amendment included concomitment medications.
    08 May 2006
    It was done to clarify inclusion criteria for pancreatic cancer and bring disease assessment in line with the progression assessment endpoint timing.

    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
    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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