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    Clinical Trial Results:
    A randomized double-blind, placebo-controlled study of everolimus in combination with exemestane in the treatment of postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrozole Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    2008-008698-69
    Trial protocol
    IT   CZ   NL   FR   BE   GB   DE   SE   ES   HU   AT  
    Global end of trial date
    04 Dec 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001Y2301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00863655
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH- 4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the combination treatment of everolimus and exemestane to exemestane alone with respect to progression-free survival (PFS) in postmenopausal women with ERpositive breast cancer that is refractory to NSAIs
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Jun 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 43
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 51
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    Egypt: 6
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Japan: 106
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Thailand: 18
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    United States: 223
    Worldwide total number of subjects
    724
    EEA total number of subjects
    278
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    449
    From 65 to 84 years
    263
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Although 724 patients were randomized, 4 never received any study treatment and thus were excluded form the safety set.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Everolimus + Exemestane
    Arm description
    Everolimus 10 mg daily in combination with exemestane 25 mg daily
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10-mg oral daily dosing regimen (two 5-mg tablets)

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

    Arm title
    Placebo + Exemestane
    Arm description
    Placebo of everolimus in combination with exemestane 25 mg daily
    Arm type
    Placebo

    Investigational medicinal product name
    Everolimus Placebo
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    oral daily dosing of two 5-mg tablets. Placebo was formulated to be indistinguishable from the everolimus tablets.

    Number of subjects in period 1
    Everolimus + Exemestane Placebo + Exemestane
    Started
    485
    239
    Completed
    0
    0
    Not completed
    485
    239
         Protocol deviation
    4
    -
         New cancer therapy
    5
    1
         Adverse event, serious fatal
    7
    1
         Administrative problems
    1
    -
         Adverse event, non-fatal
    52
    8
         Treatment completed as per protocol
    5
    1
         Consent withdrawn by subject
    47
    7
         Disease progression
    364
    221

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus + Exemestane
    Reporting group description
    Everolimus 10 mg daily in combination with exemestane 25 mg daily

    Reporting group title
    Placebo + Exemestane
    Reporting group description
    Placebo of everolimus in combination with exemestane 25 mg daily

    Reporting group values
    Everolimus + Exemestane Placebo + Exemestane Total
    Number of subjects
    485 239 724
    Age, Customized
    Units: Participants
        < 65 years
    290 159 449
        >= 65 years
    195 80 275
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    62.5 ± 10.31 61.2 ± 9.75 -
    Gender, Male/Female
    Units: participants
        Female
    485 239 724
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Everolimus + Exemestane
    Reporting group description
    Everolimus 10 mg daily in combination with exemestane 25 mg daily

    Reporting group title
    Placebo + Exemestane
    Reporting group description
    Placebo of everolimus in combination with exemestane 25 mg daily

    Primary: Progression-free survival (PFS) based on local radiology review of tumor assessments.

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    End point title
    Progression-free survival (PFS) based on local radiology review of tumor assessments.
    End point description
    Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.0). For patients with no target lesion, in the absence of new lesions, the overall lesion response at each assessment was one of following: Complete Response CR), Stable Disease SD), Unknown, or Progressive Disease (PD) based on non-target lesion responses. The following is considered progression among patients with lytic or mixed (lytic+sclerotic) bone lesions: appearance of ≥1 new lytic lesions in bone; the appearance of ≥ new lesions outside of bone and unequivocal progression of existing bone lesions.
    End point type
    Primary
    End point timeframe
    date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first ,reported between day of first patient randomized, 27 July 2009, until cut-off date 11 February 2011.
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: months
        median (confidence interval 95%)
    6.93 (6.44 to 8.05)
    2.83 (2.76 to 4.14)
    Statistical analysis title
    Progression free survival analysis
    Comparison groups
    Everolimus + Exemestane v Placebo + Exemestane
    Number of subjects included in analysis
    724
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.54

    Secondary: Overall survival (OS) by number of deaths

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    End point title
    Overall survival (OS) by number of deaths
    End point description
    Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    up to 53 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Participants
    267
    143
    No statistical analyses for this end point

    Secondary: Overall survival (OS) by median

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    End point title
    Overall survival (OS) by median
    End point description
    Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    up to 53 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Months
        median (confidence interval 95%)
    30.98 (27.96 to 34.56)
    26.55 (22.57 to 33.08)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR)

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    End point title
    Overall response rate (ORR)
    End point description
    Overall response rate (ORR) is the percentage of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.0.
    End point type
    Secondary
    End point timeframe
    up to 21 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Percentage of participants
        number (not applicable)
    9.5
    0.4
    No statistical analyses for this end point

    Secondary: Clinical benefit rate (CBR)

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    End point title
    Clinical benefit rate (CBR)
    End point description
    CBR is defined as the percentage of patients with best overall response of either complete response (CR), a partial response (PR) or stable disease (SD) >= 24 weeks, according to RECIST 1.0.
    End point type
    Secondary
    End point timeframe
    up to 21 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Percentage of participants
        number (not applicable)
    33.4
    18
    No statistical analyses for this end point

    Secondary: Time to deterioration of Eastern Cooperative Oncology Group performance status (ECOG PS) using Kaplan-Meier

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    End point title
    Time to deterioration of Eastern Cooperative Oncology Group performance status (ECOG PS) using Kaplan-Meier
    End point description
    ECOG PS scale was used to assess physical health of patients. The ECOG performance status Scale Index allows patients to be classified. ECOG scale index: 0 - Fully active, able to carry on all pre-disease performance without restriction. 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work. 2 - Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 - Dead
    End point type
    Secondary
    End point timeframe
    2, 4, 6, 9 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Percentage of participants
    median (confidence interval 95%)
        2 Months
    0.84 (0.8 to 0.87)
    0.87 (0.82 to 0.91)
        4 Months
    0.74 (0.7 to 0.78)
    0.8 (0.73 to 0.85)
        6 Months
    0.64 (0.58 to 0.69)
    0.67 (0.57 to 0.75)
        9 Months
    0.57 (0.5 to 0.63)
    0.47 (0.32 to 0.61)
    No statistical analyses for this end point

    Secondary: Patient-reported outcomes (PROs): Time to deterioration of PRO scores using Kaplan Meier: EORTC QLQ-C30

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    End point title
    Patient-reported outcomes (PROs): Time to deterioration of PRO scores using Kaplan Meier: EORTC QLQ-C30
    End point description
    The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 5 functional scales, 3 symptom scales, a global health status - QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. All of the scales measures range in score from 0 to 100. A high scale score = higher response level. Thus a high score for a functional scale represents a healthy level of function, a high score for the global health status / QoL represents a high quality of life but a high score for a symptom scale / item represents a high level of symptomatology / problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100; a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.
    End point type
    Secondary
    End point timeframe
    Up to 21 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Percentage of participants
    median (confidence interval 95%)
        Deterioration global health status score ≥ 5%
    4.53 (4.17 to 5.68)
    4.4 (3.58 to 5.85)
        Deterioration in PF domain score of ≥ 5%
    4.83 (4.17 to 6.97)
    4.37 (2.83 to 7)
        Deterioration in EF domain score of ≥ 5%
    6.93 (5.55 to 8.41)
    6.93 (4.17 to 7.36)
        Deterioration in SF domain score of ≥ 5%
    8.34 (6.93 to 10.87)
    7.03 (5.62 to 9999.99)
    No statistical analyses for this end point

    Secondary: Time to Overall response based on Investigator per Kaplan Meier

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    End point title
    Time to Overall response based on Investigator per Kaplan Meier
    End point description
    overall response = complete response (CR) + partial response (PR) per RECIST 1.0 Time to overall response (CR or PR) based on investigator is the time between date of randomization/start of treatment until first documented response (CR or PR). This analysis included all patients/responders. Patients who did not achieve a confirmed PR or CR were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (i.e. FPFV to LPLV used for the analysis) when they had an event for progression-free survival.
    End point type
    Secondary
    End point timeframe
    2, 4, 6, 9 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Months
    arithmetic mean (confidence interval 95%)
        2 months
    0.96 (0.94 to 0.98)
    1 (0.97 to 1)
        4 months
    0.93 (0.91 to 0.95)
    1 (0.97 to 1)
        6 months
    0.92 (0.89 to 0.94)
    1 (0.97 to 1)
        9 months
    0.9 (0.88 to 0.93)
    1 (0.97 to 1)
    No statistical analyses for this end point

    Secondary: Duration of overall response based on Investigator

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    End point title
    Duration of overall response based on Investigator
    End point description
    Duration of overall response (CR or PR) based on investigator applies only to patients whose best overall response was CR or PR (RECIST 1.0). The start date was the date of first documented response (CR or PR) and the end date and censoring is defined the same as that for time to progression.
    End point type
    Secondary
    End point timeframe
    up to 21 months
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    485
    239
    Units: Months
        median (confidence interval 95%)
    8.21 (5.55 to 99999.99)
    9999.99 (-99999.99 to 99999.99)
    No statistical analyses for this end point

    Secondary: Everolimus Concentrations at Week 4

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    End point title
    Everolimus Concentrations at Week 4 [1]
    End point description
    Characterize the pharmacokinetics (PK) of everolimus in combination with exemestane using Cmin (pre-dose) and C2h (post-dose) at week 4 in a small group of patients.
    End point type
    Secondary
    End point timeframe
    pre-dose, 2 hours post-dose
    Notes
    [1] - 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: Summary statistics was not done for this endpoint or on the placebo arm.
    End point values
    Everolimus + Exemestane
    Number of subjects analysed
    24
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-dose (Cmin) (n:22)
    16.04 ± 9.356
        2 hours post-dose (C2h) (n:24)
    46.5 ± 17.954
    No statistical analyses for this end point

    Secondary: Exemestane concentrations at week 4

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    End point title
    Exemestane concentrations at week 4
    End point description
    Characterize the PK of exemestane in combination with or without everolimus using Cmin and C2h at week 4 in a small group of patients.
    End point type
    Secondary
    End point timeframe
    predose, 2 hours post-dose
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    39
    22
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-dose (Cmin) (n: 34, n: 22)
    0.63 ± 0.474
    0.43 ± 0.376
        2 hours post-dose (C2h) (n: 39, n: 22)
    23.16 ± 19.805
    13.3 ± 11.889
    No statistical analyses for this end point

    Secondary: Estradiol plasma concentrations

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    End point title
    Estradiol plasma concentrations
    End point description
    Compare estradiol concentrations from baseline to week 4 in both treatment arms.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    Everolimus + Exemestane Placebo + Exemestane
    Number of subjects analysed
    41
    15
    Units: pg/mL
    arithmetic mean (standard deviation)
        Baseline (n: 41, 14)
    5.62 ± 3.342
    4.09 ± 1.792
        Week 4 (n: 38, 15)
    3.5 ± 2.551
    5.17 ± 6.919
    No statistical analyses for this end point

    Adverse events

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

    Reporting group title
    Everolimus 10mg + exemestane
    Reporting group description
    Everolimus 10mg + exemestane

    Serious adverse events
    Placebo + exemestane Everolimus 10mg + exemestane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 238 (15.55%)
    158 / 482 (32.78%)
         number of deaths (all causes)
    4
    22
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Embolism arterial
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accelerated hypertension
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 238 (0.00%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Preventive surgery
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to eye
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pituitary tumour benign
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 238 (0.00%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 238 (0.00%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 238 (1.68%)
    7 / 482 (1.45%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fractured sacrum
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 238 (1.26%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary radiation injury
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 238 (0.84%)
    12 / 482 (2.49%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 238 (0.42%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 238 (0.00%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 238 (0.00%)
    13 / 482 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 238 (0.42%)
    8 / 482 (1.66%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 238 (0.84%)
    8 / 482 (1.66%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tremor
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery thrombosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 238 (0.00%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 238 (0.00%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 238 (0.84%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine ulcer
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 238 (1.26%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 238 (0.00%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 238 (0.00%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blister
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 238 (0.42%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histoplasmosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 238 (0.42%)
    11 / 482 (2.28%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pyometra
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 238 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + exemestane Everolimus 10mg + exemestane
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    209 / 238 (87.82%)
    479 / 482 (99.38%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    34 / 238 (14.29%)
    31 / 482 (6.43%)
         occurrences all number
    38
    33
    Lymphoedema
         subjects affected / exposed
    3 / 238 (1.26%)
    30 / 482 (6.22%)
         occurrences all number
    3
    33
    Hypertension
         subjects affected / exposed
    9 / 238 (3.78%)
    49 / 482 (10.17%)
         occurrences all number
    9
    59
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 238 (4.62%)
    66 / 482 (13.69%)
         occurrences all number
    12
    87
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 238 (5.46%)
    75 / 482 (15.56%)
         occurrences all number
    13
    89
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 238 (5.04%)
    18 / 482 (3.73%)
         occurrences all number
    12
    28
    Blood creatinine increased
         subjects affected / exposed
    3 / 238 (1.26%)
    41 / 482 (8.51%)
         occurrences all number
    3
    53
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 238 (1.68%)
    30 / 482 (6.22%)
         occurrences all number
    5
    44
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    20 / 238 (8.40%)
    53 / 482 (11.00%)
         occurrences all number
    23
    67
    Weight decreased
         subjects affected / exposed
    17 / 238 (7.14%)
    136 / 482 (28.22%)
         occurrences all number
    17
    142
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    25 / 238 (10.50%)
    105 / 482 (21.78%)
         occurrences all number
    25
    124
    Cough
         subjects affected / exposed
    27 / 238 (11.34%)
    129 / 482 (26.76%)
         occurrences all number
    28
    169
    Epistaxis
         subjects affected / exposed
    3 / 238 (1.26%)
    86 / 482 (17.84%)
         occurrences all number
    3
    117
    Pneumonitis
         subjects affected / exposed
    0 / 238 (0.00%)
    73 / 482 (15.15%)
         occurrences all number
    0
    81
    Oropharyngeal pain
         subjects affected / exposed
    7 / 238 (2.94%)
    29 / 482 (6.02%)
         occurrences all number
    7
    40
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    4 / 238 (1.68%)
    29 / 482 (6.02%)
         occurrences all number
    4
    37
    Anaemia
         subjects affected / exposed
    11 / 238 (4.62%)
    101 / 482 (20.95%)
         occurrences all number
    13
    118
    Neutropenia
         subjects affected / exposed
    4 / 238 (1.68%)
    40 / 482 (8.30%)
         occurrences all number
    4
    51
    Thrombocytopenia
         subjects affected / exposed
    1 / 238 (0.42%)
    63 / 482 (13.07%)
         occurrences all number
    1
    84
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 238 (6.72%)
    38 / 482 (7.88%)
         occurrences all number
    17
    44
    Headache
         subjects affected / exposed
    35 / 238 (14.71%)
    112 / 482 (23.24%)
         occurrences all number
    44
    156
    Dysgeusia
         subjects affected / exposed
    14 / 238 (5.88%)
    106 / 482 (21.99%)
         occurrences all number
    14
    115
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 238 (4.62%)
    70 / 482 (14.52%)
         occurrences all number
    11
    84
    Fatigue
         subjects affected / exposed
    65 / 238 (27.31%)
    180 / 482 (37.34%)
         occurrences all number
    72
    213
    Oedema peripheral
         subjects affected / exposed
    15 / 238 (6.30%)
    103 / 482 (21.37%)
         occurrences all number
    16
    127
    Pyrexia
         subjects affected / exposed
    13 / 238 (5.46%)
    82 / 482 (17.01%)
         occurrences all number
    14
    120
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 238 (2.52%)
    25 / 482 (5.19%)
         occurrences all number
    6
    26
    Depression
         subjects affected / exposed
    11 / 238 (4.62%)
    28 / 482 (5.81%)
         occurrences all number
    12
    32
    Insomnia
         subjects affected / exposed
    21 / 238 (8.82%)
    68 / 482 (14.11%)
         occurrences all number
    24
    70
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 238 (4.62%)
    25 / 482 (5.19%)
         occurrences all number
    11
    29
    Abdominal pain upper
         subjects affected / exposed
    7 / 238 (2.94%)
    39 / 482 (8.09%)
         occurrences all number
    8
    44
    Diarrhoea
         subjects affected / exposed
    44 / 238 (18.49%)
    172 / 482 (35.68%)
         occurrences all number
    55
    238
    Constipation
         subjects affected / exposed
    31 / 238 (13.03%)
    74 / 482 (15.35%)
         occurrences all number
    42
    81
    Dyspepsia
         subjects affected / exposed
    12 / 238 (5.04%)
    29 / 482 (6.02%)
         occurrences all number
    12
    33
    Nausea
         subjects affected / exposed
    69 / 238 (28.99%)
    157 / 482 (32.57%)
         occurrences all number
    84
    211
    Dry mouth
         subjects affected / exposed
    17 / 238 (7.14%)
    55 / 482 (11.41%)
         occurrences all number
    19
    62
    Vomiting
         subjects affected / exposed
    30 / 238 (12.61%)
    88 / 482 (18.26%)
         occurrences all number
    32
    121
    Stomatitis
         subjects affected / exposed
    28 / 238 (11.76%)
    286 / 482 (59.34%)
         occurrences all number
    37
    493
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 238 (1.26%)
    39 / 482 (8.09%)
         occurrences all number
    3
    41
    Nail disorder
         subjects affected / exposed
    1 / 238 (0.42%)
    40 / 482 (8.30%)
         occurrences all number
    1
    41
    Alopecia
         subjects affected / exposed
    12 / 238 (5.04%)
    51 / 482 (10.58%)
         occurrences all number
    13
    57
    Pruritus
         subjects affected / exposed
    11 / 238 (4.62%)
    64 / 482 (13.28%)
         occurrences all number
    12
    76
    Rash
         subjects affected / exposed
    16 / 238 (6.72%)
    190 / 482 (39.42%)
         occurrences all number
    20
    278
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    25 / 238 (10.50%)
    81 / 482 (16.80%)
         occurrences all number
    27
    98
    Arthralgia
         subjects affected / exposed
    41 / 238 (17.23%)
    107 / 482 (22.20%)
         occurrences all number
    45
    155
    Musculoskeletal chest pain
         subjects affected / exposed
    10 / 238 (4.20%)
    38 / 482 (7.88%)
         occurrences all number
    14
    42
    Musculoskeletal pain
         subjects affected / exposed
    17 / 238 (7.14%)
    30 / 482 (6.22%)
         occurrences all number
    19
    33
    Bone pain
         subjects affected / exposed
    15 / 238 (6.30%)
    31 / 482 (6.43%)
         occurrences all number
    20
    34
    Myalgia
         subjects affected / exposed
    16 / 238 (6.72%)
    35 / 482 (7.26%)
         occurrences all number
    20
    40
    Pain in extremity
         subjects affected / exposed
    26 / 238 (10.92%)
    52 / 482 (10.79%)
         occurrences all number
    32
    70
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 238 (2.10%)
    69 / 482 (14.32%)
         occurrences all number
    5
    91
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 238 (1.26%)
    29 / 482 (6.02%)
         occurrences all number
    3
    35
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 238 (0.84%)
    50 / 482 (10.37%)
         occurrences all number
    2
    62
    Decreased appetite
         subjects affected / exposed
    31 / 238 (13.03%)
    148 / 482 (30.71%)
         occurrences all number
    38
    169
    Hypokalaemia
         subjects affected / exposed
    4 / 238 (1.68%)
    39 / 482 (8.09%)
         occurrences all number
    4
    49
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    21 / 238 (8.82%)
    53 / 482 (11.00%)
         occurrences all number
    26
    73
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 238 (2.52%)
    32 / 482 (6.64%)
         occurrences all number
    6
    44
    Urinary tract infection
         subjects affected / exposed
    5 / 238 (2.10%)
    49 / 482 (10.17%)
         occurrences all number
    5
    60

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2010
    Amendment 1 was issued after 157 patients were randomized. Subsequently, another 567 patients were randomized to the study. The purpose was: to implement program-level and study operational changes. Program-level changes included addition of guidelines on hepatitis B virus and hepatitis C virus management, detailing hyperglycemia management and everolimus administration, and modification of guidance on the usage of CYP3A4 and/or P-glycoprotein inducers and inhibitors, study operational changes included the addition of a pre-randomization process; to clarify elements in the protocol, such as the data source for primary endpoint and definition of a “lines” in exclusion criterion; to modify exclusion criteria of patients with history of brain and central nervous system metastases and Eastern cooperative oncology group performance status time-to deterioration analysis.
    12 Dec 2011
    Amendment 2 was issued after the completion of the primary CSR. 103 patients were still receiving study therapy at the time of this amendment. The study had met its primary endpoint PFS at the interim analysis. The purpose was to make interim OS analyses results available by independent data monitoring committee (IDMC) to health authorities on their request to fully evaluate the benefit-risk assessment of everolimus in breast cancer; to add one additional interim analysis after 275 OS events (70% of the targeted total) in order to assess more mature survival; to change the frequency of tumor assessments to every 12 weeks and as clinically indicated, until disease progression after approximately 528 PFS events have been documented per response evaluation criteria in solid tumors (RECIST) by local assessment.
    23 Apr 2014
    Amendment 3 was issued after the final OS CSR. Nine patients were still receiving study therapy at the time of this amendment. The study had met its primary (PFS) and reported key secondary endpoints (OS).The purpose of the amendment was to close out the study after collecting required safety data from the patients who were still receiving study treatment and transitioning them to commercially available drugs.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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