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    Clinical Trial Results:
    An open-label, multicenter phase II study to compare the efficacy and safety of RAD001 as first-line followed by second-line sunitinib versus sunitinib as first-line followed by second-line RAD001 in the treatment of patients with metastatic renal cell carcinoma Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results

    Summary
    EudraCT number
    2009-011056-21
    Trial protocol
    DK   ES   GB   DE   IT   FR   NL  
    Global end of trial date
    20 May 2015

    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
    CRAD001L2202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00903175
    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
    20 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the probability that progression-free survival (PFS) during or after first-line treatment (PFS-1L) in patients who received everolimus was non-inferior to PFS during or after first-line treatment in patients who received sunitinib as treatment for metastatic renal cell carcinoma (mRCC).
    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
    13 Oct 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
    Argentina: 12
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Brazil: 39
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Hong Kong: 14
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Peru: 15
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Thailand: 13
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United States: 160
    Worldwide total number of subjects
    471
    EEA total number of subjects
    87
    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)
    279
    From 65 to 84 years
    189
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    238 patients were randomized to everolimus as 1st line followed by 2nd line sunitinib. All patients in this group were treated. 233 patients were randomized to the sunitinib as 1st line followed by 2nd line everolimus. However 2 of the 233 patients were not treated in this group.

    Pre-assignment
    Screening details
    The trial had a crossover design: first-line therapy until disease progression followed by second-line therapy until disease progression.Patients were randomized 1:1 to either everolimus-sunitinib or sunitinib-everolimus treatment sequence and were stratified by MSKCC risk criteria

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    everolimus 1L/sunitinib 2L
    Arm description
    everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)
    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
    Everolimus was administered orally at 10 mg/day. Everolimus was formulated as tablets of 5 mg strength.

    Arm title
    sunitinib 1L/everolimus 2L
    Arm description
    sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
    Arm type
    Experimental

    Investigational medicinal product name
    sunitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Sunitinib was supplied as hard gelatin capsules of 12.5 mg, 25 mg, or 50 mg strength according to local practice.

    Number of subjects in period 1
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Started
    238
    233
    Completed
    161
    142
    Not completed
    77
    91
         Protocol deviation
    3
    3
         Untreated
    -
    2
         Abnormal lab value(s)
    -
    1
         Abnormal test procedure result(s)
    1
    -
         Adverse event, serious fatal
    17
    10
         Administrative problems
    12
    13
         Adverse event, non-fatal
    36
    50
         Consent withdrawn by subject
    8
    12
    Period 2
    Period 2 title
    Period 2 - Second Line
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    everolimus 1L/sunitinib 2L
    Arm description
    everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)
    Arm type
    Experimental

    Investigational medicinal product name
    everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Capsule, hard, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was administered orally at 10 mg/day. Everolimus was formulated as tablets of 5 mg strength.

    Arm title
    sunitinib 1L/everolimus 2L
    Arm description
    sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
    Arm type
    Experimental

    Investigational medicinal product name
    sunitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Sunitinib was supplied as hard gelatin capsules of 12.5 mg, 25 mg, or 50 mg strength according to local practice.

    Number of subjects in period 2
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Started
    128
    116
    Completed
    79
    80
    Not completed
    49
    36
         Missing
    1
    -
         Adverse event, serious fatal
    5
    2
         Administrative problems
    19
    9
         Adverse event, non-fatal
    16
    20
         Consent withdrawn by subject
    7
    5
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    everolimus 1L/sunitinib 2L
    Reporting group description
    everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)

    Reporting group title
    sunitinib 1L/everolimus 2L
    Reporting group description
    sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment

    Reporting group values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L Total
    Number of subjects
    238 233 471
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    135 144 279
        From 65-84 years
    100 89 189
        85 years and over
    3 0 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    61.36 ± 12.102 60.84 ± 11.627 -
    Gender categorical
    Units: Subjects
        Female
    166 176 342
        Male
    72 57 129

    End points

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    End points reporting groups
    Reporting group title
    everolimus 1L/sunitinib 2L
    Reporting group description
    everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)

    Reporting group title
    sunitinib 1L/everolimus 2L
    Reporting group description
    sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment
    Reporting group title
    everolimus 1L/sunitinib 2L
    Reporting group description
    everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2)

    Reporting group title
    sunitinib 1L/everolimus 2L
    Reporting group description
    sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment

    Primary: Progression Free Survival First-Line (PFS 1-L)

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    End point title
    Progression Free Survival First-Line (PFS 1-L)
    End point description
    PFS_1L based on investigator assessment of radiology data by RECIST 1.0, was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause during or after first-line treatment with everolimus or sunitinib. Radiological assessments : every 12 weeks until disease progression, the start of another antineoplastic therapy or for any other reason.
    End point type
    Primary
    End point timeframe
    Time from randomization to date of first disease progression or death during or after 1-L treatment, or last tumor assessment, reported between date of 1st participant randomized until 03-sep-2012, cutoff date (i.e. when 340 PFS-1L events were observed)
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    7.85 (5.55 to 8.25)
    10.71 (8.18 to 11.53)
    Statistical analysis title
    Cox reggresssion model for PFS-1L
    Comparison groups
    everolimus 1L/sunitinib 2L v sunitinib 1L/everolimus 2L
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.15
         upper limit
    1.77
    Notes
    [1] - Primary objective was to assess the non-inferiority of everolimus as compared to Sunitinib in terms of PFS-1L & was based on Bayesian methodology. If the estimated HR for PFS-1L had a value ≤ 1.1, non-inferiority of everolimus to Sunitinib would be declared. Non-inferiority of everolimus compared with Sunitinib as a first-line therapy was not achieved. The estimated HR for PFS-1L was 1.43 which did not satisfy the protocol-defined non-inferiority margin of a HR ≤ 1.1.
    Statistical analysis title
    Cox regression model for PFS-1L
    Comparison groups
    everolimus 1L/sunitinib 2L v sunitinib 1L/everolimus 2L
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Regression, Cox
    Parameter type
    Log hazard ratio
    Point estimate
    1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.15
         upper limit
    1.77

    Secondary: Progression-free survival combined (PFS-C)

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    End point title
    Progression-free survival combined (PFS-C)
    End point description
    PFS-C (1L and 2L study drugs combined) was a composite endpoint which combined both lines of study treatment. It was defined as the time from the date of randomization to the first of the following: date of death due to any cause, or date of the first radiologically documented progression disease during or after the second-line treatment period for patients with a radiologically documented progression disease in the first-line treatment period and who had crossed-over to second-line treatment no more than 6 weeks after progression. Radiological assessments : every 12 weeks until disease progression, the start of another antineoplastic therapy or for any other reason.
    End point type
    Secondary
    End point timeframe
    Time from randomization to date of 1st disease progression during or after 2-L treatment or date of death, or last tumor assessment, reported between date of 1st participant randomized until 3 years after last patient randomized (date cutoff : 16Jun2014)
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    21.68 (15.05 to 26.71)
    22.18 (16.03 to 29.83)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was defined as the time from date of randomization to date of death due to any cause. The analysis of OS included all deaths in the FAS regardless of when they were observed.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of death from any cause, reported between the date of first participant randomized and up to 3 years after the last participant randomized (date cutoff: 16Jun2014)
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    22.41 (18.6 to 33.28)
    29.47 (22.83 to 33.05)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) - First -Line (1-L)

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    End point title
    Overall response rate (ORR) - First -Line (1-L)
    End point description
    ORR was defined as the number of participants with best overall response (BOR) of complete response (CR) or partial response (PR) and was based on investigator assessment of radiology data per RECIST. Participants with best overall response of ‘Unknown’ were treated as non-responders in the calculation of the ORR. Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Radiological assessments : every 12 weeks until disease progression, the start of another antineoplastic therapy or for any other reason.
    End point type
    Secondary
    End point timeframe
    time from first participant randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: percentage of participants
        Complete Response (CR)
    1
    3
        Partial Response (PR)
    18
    59
        Overall Response Rate (CR + PR)
    19
    62
    No statistical analyses for this end point

    Secondary: Duration of response (DoR) - First-Line (1-L)

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    End point title
    Duration of response (DoR) - First-Line (1-L)
    End point description
    Duration of overall response (CR or PR) applies only to patients whose Best Overall Response (BOR) was Complete Response (CR) or Partial Response (PR) during the first-line treatment period. The start date was the date of first documented response (CR or PR) during the first-line treatment and the end date was the date of the event defined as the first documented progression or death due to underlying cancer during or after the same treatment line.
    End point type
    Secondary
    End point timeframe
    Time from first documented response date to date of disease progression, death from any cause during or after the 1-L period or last tumor assessment, reported between the date of first participant randomized until 03-sep-2012, cut-off date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    19
    62
    Units: Months
        median (confidence interval 95%)
    13.37 (8.3 to 999)
    17.25 (11.4 to 999)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the FKSI-DRS risk score by at least 3 score units by first-line drug

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    End point title
    Time to definitive deterioration of the FKSI-DRS risk score by at least 3 score units by first-line drug
    End point description
    The Functional Assessment of Cancer Therapy – Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration was defined as a decrease by at least 3 units compared to baseline, with no later increase above this threshold observed during the 1-L of treatment. A single measure reporting a decrease of at least 3 units was considered definitive only if it was the last one available for the patient. PRO questionnaires were to be completed on day 1, day 28 of every cycle, at the end of treatment visit, at the 28-day FUP visit, and monthly thereafter for up to 3 months or until the initiation of another anticancer therapy.
    End point type
    Secondary
    End point timeframe
    Time from randomization to date of definitive deterioration (defined as no later increase above threshold observed during the 1-L period), or date of last assessment, reported between date of first patient randomized until 03-sep-2012, cutoff date)
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    12.65 (7.9 to 19.4)
    16.66 (13.7 to 999)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the FKSI-DRS risk score by at least 3 score units by first and second-line drugs combined

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    End point title
    Time to definitive deterioration of the FKSI-DRS risk score by at least 3 score units by first and second-line drugs combined
    End point description
    The Functional Assessment of Cancer Therapy – Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration was defined as a decrease by at least 3 units compared to baseline, with no later increase above this threshold observed during the 1-L or 2-L treatment. A single measure reporting a decrease of at least 3 units was considered definitive only if it was the last one available for the patient. PRO questionnaires were to be completed on day 1, day 28 of every cycle, at the end of treatment visit, at the 28-day FUP visit, and monthly thereafter for up to 3 months or until the initiation of another anticancer therapy.
    End point type
    Secondary
    End point timeframe
    Time from randomization to date of definitive deterioration (defined as no later increase above threshold observed during the 1-L or 2-L period), or date of last assessment, reported between date of first patient randomized until 03-sep-2012, cutoff date)
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    14.23 (12 to 19.4)
    15.97 (13.7 to 20.4)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the physical functioning (PF) scale of the EORTC QLQ-C30 - by First-Line (1L) drug

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    End point title
    Time to definitive deterioration of the physical functioning (PF) scale of the EORTC QLQ-C30 - by First-Line (1L) drug
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the 1-L period), or date of last assessment, reported between date of first patient randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    13.47 (7.9 to 20.6)
    14.03 (12.1 to 17.7)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the physical functioning scale of the EORTC QLQ-C30 - by First and Second-Line drugs combined

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    End point title
    Time to definitive deterioration of the physical functioning scale of the EORTC QLQ-C30 - by First and Second-Line drugs combined
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
    End point type
    Secondary
    End point timeframe
    Time from randomization to date of definitive deterioration (defined as no later increase above threshold observed during the 1-L or 2-L period), or date of last assessment, reported between date of 1st patient randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    12.25 (9.5 to 16.3)
    14.03 (12 to 17.7)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the global health status/QoL scores of the EORTC QLQ-C30 by First-Line drug

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    End point title
    Time to definitive deterioration of the global health status/QoL scores of the EORTC QLQ-C30 by First-Line drug
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the 1-L period), or date of last assessment, reported between date of first patient randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    7.92 (5.6 to 12.1)
    12.25 (7.9 to 14.1)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the global health status/QoL scores of the EORTC QLQ-C30 by First and Second-Line drugs combined

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    End point title
    Time to definitive deterioration of the global health status/QoL scores of the EORTC QLQ-C30 by First and Second-Line drugs combined
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
    End point type
    Secondary
    End point timeframe
    Time from randomization to date of definitive deterioration (defined as no later increase above threshold observed during the 1-L or 2-L period), or date of last assessment, reported between dates of 1st patient randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    10.84 (7.5 to 13.8)
    12.71 (10.5 to 14.8)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the fatigue scale of the EORTC QLQ-C30 by First-Line drug

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    End point title
    Time to definitive deterioration of the fatigue scale of the EORTC QLQ-C30 by First-Line drug
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the 1-L period), or date of last assessment, reported between date of first patient randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        median (confidence interval 95%)
    9.2 (6.2 to 12.6)
    11.37 (9.3 to 13.4)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of the fatigue scale of the EORTC QLQ-C30 by First and Second-Line drugs combined

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    End point title
    Time to definitive deterioration of the fatigue scale of the EORTC QLQ-C30 by First and Second-Line drugs combined
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant.
    End point type
    Secondary
    End point timeframe
    Time from randomization to date of definitive deterioration (defined as no later increase above threshold observed during the 1-L or 2-L period), or date of last assessment, reported between date of 1st patient randomized until 03-sep-2012, cutoff date
    End point values
    everolimus 1L/sunitinib 2L sunitinib 1L/everolimus 2L
    Number of subjects analysed
    238
    233
    Units: Months
        arithmetic mean (confidence interval 95%)
    11.56 (7.9 to 14.1)
    13.34 (10.8 to 15.9)
    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 L:ast 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
    17.0
    Reporting groups
    Reporting group title
    Everolimus 1L
    Reporting group description
    Everolimus 1L

    Reporting group title
    Sunitinib 1L
    Reporting group description
    Sunitinib 1L

    Reporting group title
    Everolimus 2L
    Reporting group description
    Everolimus 2L

    Reporting group title
    Sunitinib 2L
    Reporting group description
    Sunitinib 2L

    Serious adverse events
    Everolimus 1L Sunitinib 1L Everolimus 2L Sunitinib 2L
    Total subjects affected by serious adverse events
         subjects affected / exposed
    107 / 238 (44.96%)
    113 / 231 (48.92%)
    43 / 116 (37.07%)
    49 / 128 (38.28%)
         number of deaths (all causes)
    34
    15
    11
    12
         number of deaths resulting from adverse events
    2
    3
    0
    1
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 238 (0.00%)
    4 / 231 (1.73%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 238 (1.26%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 238 (0.84%)
    4 / 231 (1.73%)
    2 / 116 (1.72%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    5 / 238 (2.10%)
    3 / 231 (1.30%)
    2 / 116 (1.72%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    2 / 5
    3 / 3
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 238 (1.26%)
    3 / 231 (1.30%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucous membrane disorder
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 231 (1.30%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    2 / 116 (1.72%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 238 (2.52%)
    7 / 231 (3.03%)
    0 / 116 (0.00%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 7
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Oedema genital
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    3 / 238 (1.26%)
    3 / 231 (1.30%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eastern cooperative oncology group performance status worsened
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 238 (2.10%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Atrial flutter
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 238 (1.26%)
    1 / 231 (0.43%)
    2 / 116 (1.72%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    11 / 238 (4.62%)
    8 / 231 (3.46%)
    5 / 116 (4.31%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    3 / 11
    1 / 10
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 238 (1.26%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 238 (3.36%)
    7 / 231 (3.03%)
    5 / 116 (4.31%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 238 (1.68%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 238 (2.52%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 238 (6.72%)
    3 / 231 (1.30%)
    6 / 116 (5.17%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    7 / 22
    3 / 4
    4 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph node pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 238 (0.00%)
    9 / 231 (3.90%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysgeusia
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningorrhagia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    4 / 238 (1.68%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Corneal disorder
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 238 (1.26%)
    6 / 231 (2.60%)
    3 / 116 (2.59%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 6
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 231 (1.30%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 231 (1.30%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 238 (2.10%)
    5 / 231 (2.16%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal erosion
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 238 (1.26%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 238 (0.84%)
    3 / 231 (1.30%)
    3 / 116 (2.59%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    4 / 238 (1.68%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 238 (0.84%)
    6 / 231 (2.60%)
    2 / 116 (1.72%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 7
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 238 (3.36%)
    7 / 231 (3.03%)
    3 / 116 (2.59%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    3 / 8
    2 / 7
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    2 / 238 (0.84%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 238 (2.10%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal vein thrombosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 231 (1.30%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemobilia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised erythema
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 238 (1.26%)
    1 / 231 (0.43%)
    2 / 116 (1.72%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 231 (1.30%)
    0 / 116 (0.00%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral lesion
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    7 / 238 (2.94%)
    6 / 231 (2.60%)
    0 / 116 (0.00%)
    6 / 128 (4.69%)
         occurrences causally related to treatment / all
    3 / 8
    4 / 6
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Feeding disorder
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    5 / 231 (2.16%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    4 / 238 (1.68%)
    1 / 231 (0.43%)
    4 / 116 (3.45%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess oral
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial prostatitis
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Cellulitis
         subjects affected / exposed
    2 / 238 (0.84%)
    2 / 231 (0.87%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected bites
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 231 (0.43%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 238 (5.88%)
    8 / 231 (3.46%)
    7 / 116 (6.03%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    4 / 16
    0 / 8
    3 / 8
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonella sepsis
         subjects affected / exposed
    0 / 238 (0.00%)
    0 / 231 (0.00%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 238 (0.84%)
    3 / 231 (1.30%)
    1 / 116 (0.86%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 238 (1.68%)
    2 / 231 (0.87%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 238 (1.26%)
    3 / 231 (1.30%)
    2 / 116 (1.72%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 231 (0.00%)
    0 / 116 (0.00%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Everolimus 1L Sunitinib 1L Everolimus 2L Sunitinib 2L
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    230 / 238 (96.64%)
    228 / 231 (98.70%)
    107 / 116 (92.24%)
    124 / 128 (96.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 238 (10.08%)
    81 / 231 (35.06%)
    6 / 116 (5.17%)
    42 / 128 (32.81%)
         occurrences all number
    29
    121
    7
    52
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    30 / 238 (12.61%)
    53 / 231 (22.94%)
    15 / 116 (12.93%)
    20 / 128 (15.63%)
         occurrences all number
    39
    109
    17
    32
    Chills
         subjects affected / exposed
    22 / 238 (9.24%)
    17 / 231 (7.36%)
    5 / 116 (4.31%)
    8 / 128 (6.25%)
         occurrences all number
    28
    17
    5
    10
    Face oedema
         subjects affected / exposed
    6 / 238 (2.52%)
    18 / 231 (7.79%)
    1 / 116 (0.86%)
    9 / 128 (7.03%)
         occurrences all number
    6
    32
    1
    12
    Fatigue
         subjects affected / exposed
    108 / 238 (45.38%)
    122 / 231 (52.81%)
    40 / 116 (34.48%)
    49 / 128 (38.28%)
         occurrences all number
    137
    204
    47
    69
    Non-cardiac chest pain
         subjects affected / exposed
    23 / 238 (9.66%)
    22 / 231 (9.52%)
    11 / 116 (9.48%)
    11 / 128 (8.59%)
         occurrences all number
    26
    24
    13
    13
    Oedema peripheral
         subjects affected / exposed
    60 / 238 (25.21%)
    42 / 231 (18.18%)
    23 / 116 (19.83%)
    26 / 128 (20.31%)
         occurrences all number
    93
    60
    35
    39
    Peripheral swelling
         subjects affected / exposed
    12 / 238 (5.04%)
    6 / 231 (2.60%)
    5 / 116 (4.31%)
    3 / 128 (2.34%)
         occurrences all number
    13
    7
    5
    3
    Pyrexia
         subjects affected / exposed
    53 / 238 (22.27%)
    33 / 231 (14.29%)
    17 / 116 (14.66%)
    18 / 128 (14.06%)
         occurrences all number
    73
    40
    22
    26
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    18 / 238 (7.56%)
    16 / 231 (6.93%)
    4 / 116 (3.45%)
    4 / 128 (3.13%)
         occurrences all number
    20
    18
    4
    4
    Depression
         subjects affected / exposed
    16 / 238 (6.72%)
    10 / 231 (4.33%)
    3 / 116 (2.59%)
    4 / 128 (3.13%)
         occurrences all number
    16
    10
    3
    4
    Insomnia
         subjects affected / exposed
    36 / 238 (15.13%)
    28 / 231 (12.12%)
    13 / 116 (11.21%)
    8 / 128 (6.25%)
         occurrences all number
    44
    35
    13
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 238 (5.46%)
    15 / 231 (6.49%)
    4 / 116 (3.45%)
    3 / 128 (2.34%)
         occurrences all number
    15
    19
    4
    3
    Blood creatinine increased
         subjects affected / exposed
    30 / 238 (12.61%)
    28 / 231 (12.12%)
    15 / 116 (12.93%)
    3 / 128 (2.34%)
         occurrences all number
    34
    51
    17
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 238 (4.20%)
    13 / 231 (5.63%)
    4 / 116 (3.45%)
    5 / 128 (3.91%)
         occurrences all number
    10
    16
    5
    5
    Haemoglobin decreased
         subjects affected / exposed
    18 / 238 (7.56%)
    19 / 231 (8.23%)
    9 / 116 (7.76%)
    5 / 128 (3.91%)
         occurrences all number
    26
    25
    17
    6
    Neutrophil count decreased
         subjects affected / exposed
    0 / 238 (0.00%)
    15 / 231 (6.49%)
    1 / 116 (0.86%)
    7 / 128 (5.47%)
         occurrences all number
    0
    21
    1
    8
    Platelet count decreased
         subjects affected / exposed
    0 / 238 (0.00%)
    17 / 231 (7.36%)
    0 / 116 (0.00%)
    6 / 128 (4.69%)
         occurrences all number
    0
    31
    0
    8
    Weight decreased
         subjects affected / exposed
    53 / 238 (22.27%)
    36 / 231 (15.58%)
    14 / 116 (12.07%)
    16 / 128 (12.50%)
         occurrences all number
    56
    42
    14
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    62 / 238 (26.05%)
    50 / 231 (21.65%)
    33 / 116 (28.45%)
    18 / 128 (14.06%)
         occurrences all number
    88
    71
    43
    23
    Leukopenia
         subjects affected / exposed
    7 / 238 (2.94%)
    14 / 231 (6.06%)
    1 / 116 (0.86%)
    6 / 128 (4.69%)
         occurrences all number
    7
    17
    4
    7
    Neutropenia
         subjects affected / exposed
    8 / 238 (3.36%)
    44 / 231 (19.05%)
    4 / 116 (3.45%)
    16 / 128 (12.50%)
         occurrences all number
    10
    73
    4
    23
    Thrombocytopenia
         subjects affected / exposed
    10 / 238 (4.20%)
    57 / 231 (24.68%)
    4 / 116 (3.45%)
    30 / 128 (23.44%)
         occurrences all number
    18
    95
    6
    39
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    91 / 238 (38.24%)
    55 / 231 (23.81%)
    28 / 116 (24.14%)
    19 / 128 (14.84%)
         occurrences all number
    126
    71
    32
    27
    Dyspnoea
         subjects affected / exposed
    57 / 238 (23.95%)
    39 / 231 (16.88%)
    24 / 116 (20.69%)
    19 / 128 (14.84%)
         occurrences all number
    70
    46
    25
    24
    Dyspnoea exertional
         subjects affected / exposed
    13 / 238 (5.46%)
    10 / 231 (4.33%)
    7 / 116 (6.03%)
    6 / 128 (4.69%)
         occurrences all number
    13
    12
    8
    6
    Epistaxis
         subjects affected / exposed
    43 / 238 (18.07%)
    46 / 231 (19.91%)
    12 / 116 (10.34%)
    13 / 128 (10.16%)
         occurrences all number
    60
    75
    16
    28
    Oropharyngeal pain
         subjects affected / exposed
    23 / 238 (9.66%)
    12 / 231 (5.19%)
    10 / 116 (8.62%)
    8 / 128 (6.25%)
         occurrences all number
    27
    14
    10
    8
    Pneumonitis
         subjects affected / exposed
    16 / 238 (6.72%)
    0 / 231 (0.00%)
    7 / 116 (6.03%)
    0 / 128 (0.00%)
         occurrences all number
    20
    0
    7
    0
    Productive cough
         subjects affected / exposed
    18 / 238 (7.56%)
    10 / 231 (4.33%)
    11 / 116 (9.48%)
    9 / 128 (7.03%)
         occurrences all number
    22
    11
    15
    9
    Rhinorrhoea
         subjects affected / exposed
    20 / 238 (8.40%)
    11 / 231 (4.76%)
    7 / 116 (6.03%)
    7 / 128 (5.47%)
         occurrences all number
    25
    12
    10
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 238 (13.03%)
    25 / 231 (10.82%)
    9 / 116 (7.76%)
    13 / 128 (10.16%)
         occurrences all number
    38
    35
    9
    15
    Dysgeusia
         subjects affected / exposed
    53 / 238 (22.27%)
    71 / 231 (30.74%)
    8 / 116 (6.90%)
    30 / 128 (23.44%)
         occurrences all number
    60
    110
    9
    38
    Headache
         subjects affected / exposed
    47 / 238 (19.75%)
    43 / 231 (18.61%)
    9 / 116 (7.76%)
    17 / 128 (13.28%)
         occurrences all number
    68
    63
    9
    18
    Neuropathy peripheral
         subjects affected / exposed
    6 / 238 (2.52%)
    12 / 231 (5.19%)
    2 / 116 (1.72%)
    5 / 128 (3.91%)
         occurrences all number
    6
    13
    3
    6
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    2 / 238 (0.84%)
    11 / 231 (4.76%)
    1 / 116 (0.86%)
    7 / 128 (5.47%)
         occurrences all number
    2
    13
    1
    13
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    7 / 238 (2.94%)
    4 / 231 (1.73%)
    4 / 116 (3.45%)
    7 / 128 (5.47%)
         occurrences all number
    8
    4
    4
    7
    Abdominal distension
         subjects affected / exposed
    9 / 238 (3.78%)
    15 / 231 (6.49%)
    1 / 116 (0.86%)
    10 / 128 (7.81%)
         occurrences all number
    9
    18
    2
    15
    Abdominal pain
         subjects affected / exposed
    40 / 238 (16.81%)
    33 / 231 (14.29%)
    13 / 116 (11.21%)
    15 / 128 (11.72%)
         occurrences all number
    50
    40
    16
    22
    Abdominal pain upper
         subjects affected / exposed
    21 / 238 (8.82%)
    32 / 231 (13.85%)
    4 / 116 (3.45%)
    12 / 128 (9.38%)
         occurrences all number
    23
    42
    4
    14
    Aphthous stomatitis
         subjects affected / exposed
    14 / 238 (5.88%)
    1 / 231 (0.43%)
    1 / 116 (0.86%)
    0 / 128 (0.00%)
         occurrences all number
    19
    1
    2
    0
    Constipation
         subjects affected / exposed
    48 / 238 (20.17%)
    57 / 231 (24.68%)
    14 / 116 (12.07%)
    23 / 128 (17.97%)
         occurrences all number
    55
    71
    16
    31
    Diarrhoea
         subjects affected / exposed
    92 / 238 (38.66%)
    134 / 231 (58.01%)
    17 / 116 (14.66%)
    69 / 128 (53.91%)
         occurrences all number
    151
    361
    22
    125
    Dry mouth
         subjects affected / exposed
    13 / 238 (5.46%)
    18 / 231 (7.79%)
    4 / 116 (3.45%)
    3 / 128 (2.34%)
         occurrences all number
    16
    21
    4
    4
    Dyspepsia
         subjects affected / exposed
    12 / 238 (5.04%)
    56 / 231 (24.24%)
    7 / 116 (6.03%)
    25 / 128 (19.53%)
         occurrences all number
    16
    82
    9
    28
    Dysphagia
         subjects affected / exposed
    14 / 238 (5.88%)
    8 / 231 (3.46%)
    4 / 116 (3.45%)
    2 / 128 (1.56%)
         occurrences all number
    14
    8
    4
    2
    Gastritis
         subjects affected / exposed
    6 / 238 (2.52%)
    12 / 231 (5.19%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences all number
    6
    19
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 238 (2.52%)
    24 / 231 (10.39%)
    4 / 116 (3.45%)
    9 / 128 (7.03%)
         occurrences all number
    9
    29
    4
    9
    Mouth ulceration
         subjects affected / exposed
    16 / 238 (6.72%)
    7 / 231 (3.03%)
    8 / 116 (6.90%)
    5 / 128 (3.91%)
         occurrences all number
    20
    9
    15
    9
    Nausea
         subjects affected / exposed
    83 / 238 (34.87%)
    115 / 231 (49.78%)
    21 / 116 (18.10%)
    48 / 128 (37.50%)
         occurrences all number
    104
    193
    25
    82
    Oral pain
         subjects affected / exposed
    7 / 238 (2.94%)
    12 / 231 (5.19%)
    1 / 116 (0.86%)
    7 / 128 (5.47%)
         occurrences all number
    7
    17
    1
    11
    Stomatitis
         subjects affected / exposed
    125 / 238 (52.52%)
    135 / 231 (58.44%)
    37 / 116 (31.90%)
    36 / 128 (28.13%)
         occurrences all number
    197
    267
    49
    48
    Vomiting
         subjects affected / exposed
    48 / 238 (20.17%)
    67 / 231 (29.00%)
    9 / 116 (7.76%)
    34 / 128 (26.56%)
         occurrences all number
    77
    119
    13
    77
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    16 / 238 (6.72%)
    11 / 231 (4.76%)
    5 / 116 (4.31%)
    3 / 128 (2.34%)
         occurrences all number
    19
    12
    5
    3
    Haematuria
         subjects affected / exposed
    5 / 238 (2.10%)
    16 / 231 (6.93%)
    2 / 116 (1.72%)
    7 / 128 (5.47%)
         occurrences all number
    6
    18
    4
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 238 (2.94%)
    15 / 231 (6.49%)
    0 / 116 (0.00%)
    9 / 128 (7.03%)
         occurrences all number
    7
    15
    0
    9
    Dermatitis acneiform
         subjects affected / exposed
    18 / 238 (7.56%)
    6 / 231 (2.60%)
    4 / 116 (3.45%)
    3 / 128 (2.34%)
         occurrences all number
    26
    6
    4
    5
    Dry skin
         subjects affected / exposed
    26 / 238 (10.92%)
    31 / 231 (13.42%)
    8 / 116 (6.90%)
    8 / 128 (6.25%)
         occurrences all number
    31
    37
    12
    14
    Erythema
         subjects affected / exposed
    8 / 238 (3.36%)
    15 / 231 (6.49%)
    4 / 116 (3.45%)
    4 / 128 (3.13%)
         occurrences all number
    9
    17
    7
    6
    Hair colour changes
         subjects affected / exposed
    1 / 238 (0.42%)
    16 / 231 (6.93%)
    1 / 116 (0.86%)
    5 / 128 (3.91%)
         occurrences all number
    1
    17
    1
    7
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    13 / 238 (5.46%)
    92 / 231 (39.83%)
    2 / 116 (1.72%)
    37 / 128 (28.91%)
         occurrences all number
    13
    271
    2
    80
    Pruritus
         subjects affected / exposed
    41 / 238 (17.23%)
    29 / 231 (12.55%)
    11 / 116 (9.48%)
    4 / 128 (3.13%)
         occurrences all number
    50
    31
    12
    5
    Rash
         subjects affected / exposed
    89 / 238 (37.39%)
    56 / 231 (24.24%)
    22 / 116 (18.97%)
    18 / 128 (14.06%)
         occurrences all number
    150
    93
    30
    23
    Skin discolouration
         subjects affected / exposed
    1 / 238 (0.42%)
    11 / 231 (4.76%)
    0 / 116 (0.00%)
    8 / 128 (6.25%)
         occurrences all number
    1
    13
    0
    13
    Yellow skin
         subjects affected / exposed
    1 / 238 (0.42%)
    28 / 231 (12.12%)
    0 / 116 (0.00%)
    11 / 128 (8.59%)
         occurrences all number
    1
    31
    0
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    39 / 238 (16.39%)
    30 / 231 (12.99%)
    15 / 116 (12.93%)
    19 / 128 (14.84%)
         occurrences all number
    49
    44
    17
    25
    Back pain
         subjects affected / exposed
    46 / 238 (19.33%)
    54 / 231 (23.38%)
    19 / 116 (16.38%)
    19 / 128 (14.84%)
         occurrences all number
    60
    70
    20
    24
    Flank pain
         subjects affected / exposed
    17 / 238 (7.14%)
    12 / 231 (5.19%)
    7 / 116 (6.03%)
    8 / 128 (6.25%)
         occurrences all number
    19
    16
    9
    8
    Muscle spasms
         subjects affected / exposed
    10 / 238 (4.20%)
    10 / 231 (4.33%)
    1 / 116 (0.86%)
    8 / 128 (6.25%)
         occurrences all number
    11
    16
    3
    9
    Muscular weakness
         subjects affected / exposed
    6 / 238 (2.52%)
    12 / 231 (5.19%)
    3 / 116 (2.59%)
    9 / 128 (7.03%)
         occurrences all number
    7
    13
    3
    9
    Musculoskeletal chest pain
         subjects affected / exposed
    10 / 238 (4.20%)
    7 / 231 (3.03%)
    4 / 116 (3.45%)
    8 / 128 (6.25%)
         occurrences all number
    12
    11
    4
    8
    Musculoskeletal pain
         subjects affected / exposed
    19 / 238 (7.98%)
    17 / 231 (7.36%)
    4 / 116 (3.45%)
    11 / 128 (8.59%)
         occurrences all number
    20
    19
    4
    13
    Myalgia
         subjects affected / exposed
    14 / 238 (5.88%)
    18 / 231 (7.79%)
    6 / 116 (5.17%)
    6 / 128 (4.69%)
         occurrences all number
    15
    25
    6
    8
    Neck pain
         subjects affected / exposed
    9 / 238 (3.78%)
    12 / 231 (5.19%)
    2 / 116 (1.72%)
    1 / 128 (0.78%)
         occurrences all number
    11
    13
    3
    1
    Pain in extremity
         subjects affected / exposed
    32 / 238 (13.45%)
    36 / 231 (15.58%)
    11 / 116 (9.48%)
    20 / 128 (15.63%)
         occurrences all number
    43
    55
    13
    30
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 238 (0.84%)
    14 / 231 (6.06%)
    0 / 116 (0.00%)
    2 / 128 (1.56%)
         occurrences all number
    2
    15
    0
    2
    Hypothyroidism
         subjects affected / exposed
    5 / 238 (2.10%)
    56 / 231 (24.24%)
    1 / 116 (0.86%)
    25 / 128 (19.53%)
         occurrences all number
    5
    57
    1
    27
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    75 / 238 (31.51%)
    82 / 231 (35.50%)
    32 / 116 (27.59%)
    40 / 128 (31.25%)
         occurrences all number
    93
    130
    34
    53
    Dehydration
         subjects affected / exposed
    12 / 238 (5.04%)
    21 / 231 (9.09%)
    4 / 116 (3.45%)
    7 / 128 (5.47%)
         occurrences all number
    13
    27
    5
    12
    Hypercholesterolaemia
         subjects affected / exposed
    19 / 238 (7.98%)
    8 / 231 (3.46%)
    5 / 116 (4.31%)
    0 / 128 (0.00%)
         occurrences all number
    22
    8
    5
    0
    Hyperglycaemia
         subjects affected / exposed
    37 / 238 (15.55%)
    13 / 231 (5.63%)
    17 / 116 (14.66%)
    6 / 128 (4.69%)
         occurrences all number
    51
    22
    20
    7
    Hyperkalaemia
         subjects affected / exposed
    10 / 238 (4.20%)
    10 / 231 (4.33%)
    6 / 116 (5.17%)
    4 / 128 (3.13%)
         occurrences all number
    10
    14
    6
    8
    Hypertriglyceridaemia
         subjects affected / exposed
    17 / 238 (7.14%)
    12 / 231 (5.19%)
    4 / 116 (3.45%)
    6 / 128 (4.69%)
         occurrences all number
    20
    22
    5
    6
    Infections and infestations
    Influenza
         subjects affected / exposed
    12 / 238 (5.04%)
    6 / 231 (2.60%)
    2 / 116 (1.72%)
    4 / 128 (3.13%)
         occurrences all number
    14
    6
    2
    4
    Nasopharyngitis
         subjects affected / exposed
    24 / 238 (10.08%)
    16 / 231 (6.93%)
    2 / 116 (1.72%)
    3 / 128 (2.34%)
         occurrences all number
    30
    17
    2
    6
    Pneumonia
         subjects affected / exposed
    12 / 238 (5.04%)
    2 / 231 (0.87%)
    8 / 116 (6.90%)
    4 / 128 (3.13%)
         occurrences all number
    13
    2
    9
    5
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 238 (9.24%)
    29 / 231 (12.55%)
    9 / 116 (7.76%)
    5 / 128 (3.91%)
         occurrences all number
    31
    38
    11
    5
    Urinary tract infection
         subjects affected / exposed
    19 / 238 (7.98%)
    20 / 231 (8.66%)
    5 / 116 (4.31%)
    3 / 128 (2.34%)
         occurrences all number
    30
    37
    9
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2010
    The main purpose of this amendment was the introduction of safety language standard for the everolimus clinical development program:Guidance was provided regarding the identification of patients at risk for HBV infection/reactivation, providing them with prophylactic treatment prior to and throughout everolimus therapy, and monitoring them for reactivation of HBV. Guidance on the management f patients at risk of HVC viral reactivation was also provided. A Adequate contraception was to be used while on study and for 8 weeks after the last dose of study drug. Elevations of serum creatinine had been observed in the everolimus clinical development program. Measurement of blood urea nitrogen or serum creatinine, was recommended prior to the start of therapy with everolimus and periodically thereafter. Hyperglycemia has been reported in everolimus clinical trials. Monitoring of fasting serum glucose was recommended prior to the start of everolimus therapy and periodically thereafter. Optimal glycemic control should be achieved before starting therapy. The use of live vaccines during treatment with everolimus was not recommended; immunosuppressants, including everolimus, may diminish the effectiveness of vaccination. The fatigue scale of the EORTC QLQ-C30 was added to the list of planned PRO/QoL endpoints. The recruitment period was changed from 12 months to 18 months. The maximum allowed time of the interline period was changed from 6 weeks to 35 days, to have the same time interval as the baseline assessment for second line. This change did not impact any patient on study, because no patient had finished the first-line of treatment. Administration of everolimus was to occur only after meals.
    02 Feb 2011
    The amendment revised the initial assumption of a 5% PFS-1L censoring rate. A 20% rate was assumed in the amended protocol, leading to an increase of the sample size (from 390 to 460 patients) & extension of the enrollment period, thereby ensuring that the pre-defined target number PFS-1L events would be observed by the end of the trial. For OS, a descriptive Bayesian analysis of the survival data was added in alignment with the primary efficacy analysis approach which would calculate the whole posterior distribution of HR for OS. In particular, the posterior probability for HR being inferior or equal to some threshold of interest could be reported. 1 of these thresholds of interest is the non-inferiority margin which was pre-defined as 1.06. The assumption regarding the expected cross-over rate to 2-L treatment was also revised, based on the ongoing blinded data monitoring of the trial and published results of the cross-over rates to 2-L after a 1-L treatment; >55% of patients receiving a 1-L therapy had crossed-over into 2-L therapy as reported in Motzer 2009 and Escudier 2010. The expected number of PFS events during or after 2-L was revised accordingly. In addition to the 2-sided 95% CIs, 2-sided 80% CIs would be reported for the estimated HR of the time-to-event variables for the key secondary efficacy endpoints analyses to facilitate the interpretation of results.The definition and safety recommendations concerning HBV reactivation and HCV flare were modified. The definition of HBV reactivation was amended to require only an increase of greater than 1 log10 IU/mL in HBV-DNA relative to baseline levels, and there was no longer a requirement for the increase in ALT levels. HCV flare (HCV reactivation) was removed from the study protocol. Further to recommendations made by expert hepatologists, the definition of HCV flare was amended to incorporate 2 separate clinical criteria.

    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.
    PRO Tools - completed on Days 1 & 28 of a cycle. Assessments on D1 coincided with end of a 14-day break for patients on sunitinib but not everolimus. So D1 assessments of patients in sunitinib arm may be less impacted by potential toxicity effects.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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