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    Clinical Trial Results:
    A randomized, double-blind, multi-center phase III study comparing everolimus (RAD001) plus best supportive care versus placebo plus best supportive care in patients with advanced gastric cancer after progression on prior systemic chemotherapy.

    Summary
    EudraCT number
    2008-006544-20
    Trial protocol
    NL   BE   DE   GB   FR   IT   ES  
    Global end of trial date
    30 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001R2301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00879333
    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
    30 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare overall survival between everolimus (RAD001)+best supportive care (BSC) and placebo+BSC in patients with advanced gastric cancer after progression on prior systemic chemotherapy.
    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
    Best supportive care (BSC) plus placebo was used as the comparator. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
    Actual start date of recruitment
    07 Jul 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
    Spain: 6
    Country: Number of subjects enrolled
    Taiwan: 26
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Australia: 54
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    China: 128
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Japan: 116
    Country: Number of subjects enrolled
    Korea, Republic of: 77
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Peru: 11
    Country: Number of subjects enrolled
    Russian Federation: 9
    Worldwide total number of subjects
    656
    EEA total number of subjects
    157
    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)
    389
    From 65 to 84 years
    261
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    Six hundred and fifty-six patients with advanced gastric cancer (AGC) who had progressed after one or two prior lines of systemic chemotherapy were randomized to receive either everolimus or placebo.

    Pre-assignment
    Screening details
    Adult patients with histologically or cytologically confirmed AGC which progressed after 1 or 2 prior systemic chemotherapy lines were enrolled in the study, stratified by both number of prior chemotherapy lines for advanced disease (1 line vs 2 lines) and region (Asia vs ROW). Intended samples size was 633, with 656 randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Everolimus + BSC
    Arm description
    All patients were randomized to receive everolimus (RAD001) + best supportive care (BSC). All patients took two 5 mg tablets orally of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
    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
    All patients took two 5 mg tablets of everolimus orally once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg.

    Arm title
    Placebo + BSC
    Arm description
    All patients were randomized to receive placebo + BSC. All patients took two 5 mg tablets orally of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anticancer treatments.
    Arm type
    Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All patients took two 5 mg tablets of matching placebo orally once daily. Therefore, all patients in the placebo arm received matching tablets of a total daily dose of 10 mg.

    Number of subjects in period 1
    Everolimus + BSC Placebo + BSC
    Started
    439
    217
    Completed
    11
    0
    Not completed
    428
    217
         Disease Progression
    292
    169
         Administrative Problems
    2
    -
         Withdrawal by Subject
    20
    7
         Abnormal Laboratory
    1
    -
         Adverse event, serious fatal
    16
    5
         Protocol Violation
    1
    1
         Adverse event, non-fatal
    94
    34
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus + BSC
    Reporting group description
    All patients were randomized to receive everolimus (RAD001) + best supportive care (BSC). All patients took two 5 mg tablets orally of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.

    Reporting group title
    Placebo + BSC
    Reporting group description
    All patients were randomized to receive placebo + BSC. All patients took two 5 mg tablets orally of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anticancer treatments.

    Reporting group values
    Everolimus + BSC Placebo + BSC Total
    Number of subjects
    439 217 656
    Age categorical
    Units: Subjects
        < 65 years
    260 129 389
        >=65 years
    179 88 267
    Age continuous
    The EMA result system autopopulates the “-“ and will not allow the entry of the mean age for the trial, which is 60.4 (standard deviation: 11.59).
    Units: years
        arithmetic mean (standard deviation)
    60.3 ± 11.59 60.8 ± 11.61 -
    Gender categorical
    Units: Subjects
        Female
    117 56 173
        Male
    322 161 483
    Race/Ethnicity
    Units: Subjects
        Caucasian
    166 75 241
        Black
    3 1 4
        Asian
    251 126 377
        Native American
    0 1 1
        Other
    19 14 33

    End points

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    End points reporting groups
    Reporting group title
    Everolimus + BSC
    Reporting group description
    All patients were randomized to receive everolimus (RAD001) + best supportive care (BSC). All patients took two 5 mg tablets orally of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.

    Reporting group title
    Placebo + BSC
    Reporting group description
    All patients were randomized to receive placebo + BSC. All patients took two 5 mg tablets orally of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anticancer treatments.

    Primary: Overall Survival

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    End point title
    Overall Survival
    End point description
    The primary objective of this study was to compare OS between everolimus + best supportive care (BSC) and placebo + BSC. OS, was defined as the time from date of randomization to the date of death due to any cause. If at the analysis cut-off date a patient was not known to have died, survival was censored at the date of the last contact. OS was analyzed using the Kaplan Meier estimates method. The Full Analysis Set (FAS) was used.
    End point type
    Primary
    End point timeframe
    2.5 years
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    439
    217
    Units: Months
    median (confidence interval 95%)
        Median Overall Survival (Months)
    5.39 (4.8 to 6.01)
    4.34 (3.81 to 5.49)
    Statistical analysis title
    Analysis of overall survival using K-M and Cox PH
    Statistical analysis description
    The primary analysis was a comparison of OS between the treatment groups in the FAS. The statistical hypotheses were: H0: SEverolimus(t) = SPlacebo(t) vs H1: SEverolimus(t) > SPlacebo(t), where SEverolimus(t) and SPlacebo(t) are the survival functions in everolimus + BSC and placebo + BSC groups, respectively. The null hypothesis was tested with the one-sided log-rank test using an overall type I error rate of 2.5%. Two-sided 95% CI was estimated from a Cox proportional hazard model.
    Comparison groups
    Everolimus + BSC v Placebo + BSC
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1244 [1]
    Method
    Kaplan-Meier method and Cox PH model
    Confidence interval
    Notes
    [1] - one-sided stratified log-rank test p-value

    Secondary: Progression Free Survival

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    End point title
    Progression Free Survival
    End point description
    Progression free survival is defined as time from the date of randomization to the date of the first documented disease progression or death due to any cause where progression was based on Investigator assessment of baseline and post-baseline scans according to RECIST. Progression free survival was censored if no PFS event was observed before the first to occur out of (i) the cut-off date, or (ii) the date when a further anticancer therapy was started. The censoring date was the date of the last adequate tumor assessment before either of these two events occurred. If a PFS event was observed after two or more missing or non-evaluable tumor assessments, then the date of progression was censored at the date of the last adequate tumor assessment; for a PFS event observed after a single missing or non-evaluable tumor assessment, the actual date of disease progression was used. Anslsis was done using Kaplan-Meier estimates method.
    End point type
    Secondary
    End point timeframe
    2.5 years
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    439
    217
    Units: Months
    median (confidence interval 95%)
        Progression Free Survival (months)
    1.68 (1.51 to 1.94)
    1.41 (1.38 to 1.45)
    No statistical analyses for this end point

    Secondary: Patient Reported Outcome: Time to definitive deterioration of EORTC QLQ-C30 scores

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    End point title
    Patient Reported Outcome: Time to definitive deterioration of EORTC QLQ-C30 scores
    End point description
    The EORTC QLQ-C30 global health status/quality of life sub-scale (QL) was pre-specified as the primary domain of interest, followed by physical functioning (PF), social functioning (SF) and emotional functioning (EF). The EORTC QLQ-C30 questionnaire, along with a module specific for gastric cancer patients (EORTC QLQ-STO22), was used to evaluate patient-reported outcome (PRO). The QLQ-C30 has five function scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and a global health status/quality of life scale. In addition, there are questions that assess specific symptoms. The QLQ-STO22 consists of 22 questions that make up five multi-item scales (dysphagia, pain, reflux, eating and anxiety) and four single-item scales (dry mouth, tasting, body image and hair loss).
    End point type
    Secondary
    End point timeframe
    2.5 years
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    439
    217
    Units: Months
    median (confidence interval 95%)
        In QL score by at least 5 %
    1.51 (1.28 to 1.84)
    1.45 (1.05 to 1.68)
        In PF score by at least 5 %
    1.35 (1.12 to 1.54)
    1.15 (1.02 to 1.64)
        In SF score by at least 5 %
    1.87 (1.84 to 2.3)
    1.87 (1.64 to 2.46)
        In EF score by at least 5 %
    1.84 (1.61 to 2.1)
    1.71 (1.41 to 1.87)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of Eastern Cooperative Oncology Group Performance Status

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    End point title
    Time to definitive deterioration of Eastern Cooperative Oncology Group Performance Status
    End point description
    The ECOG PS scale was used to classify patients according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). An analysis of the time to definitive deterioration of the ECOG PS by one category of the score from baseline was performed. Definitive deterioration was defined as a definitive increase by one category from baseline in ECOG PS, with no later improvements observed during the course of the study. A single measure reporting an increase in ECOG PS is sufficient to consider it as a definitive worsening only if it was the last one available for the patient. Kaplan-Meier method was used to estimate the distribution function of time to definitive worsening.
    End point type
    Secondary
    End point timeframe
    2.5 years
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    439
    217
    Units: Months
    median (confidence interval 95%)
        Time to definitive deterioration of ECOG PS Score
    2.3 (1.97 to 2.79)
    2.23 (1.87 to 2.92)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR)
    End point description
    Overall response rate (ORR) was defined as the proportion of patients with measurable disease in whom best overall response (OR) was either complete response (CR) or partial response (PR) according to RECIST criteria.
    End point type
    Secondary
    End point timeframe
    2.5 years
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    439
    217
    Units: Participants
    number (not applicable)
        Measurable Disease
    379
    191
        Complete Response (CR)
    1
    0
        Partial Response (PR)
    16
    4
        Overall Response Rate (ORR)
    17
    4
    No statistical analyses for this end point

    Secondary: Everolimus steady state concentrations at predose (Cmin) and Cmax at Week 5

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    End point title
    Everolimus steady state concentrations at predose (Cmin) and Cmax at Week 5
    End point description
    Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.
    End point type
    Secondary
    End point timeframe
    Week 5
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    218 [2]
    18 [3]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-dose (Cmin) (n: 201,18)
    16.143 ± 10.7723
    10.498 ± 6.1432
        Cmax (n: 218,16)
    72.775 ± 36.5435
    37.269 ± 27.2086
    Notes
    [2] - All PK analyses were based on the safety population in patients with evaluable samples.
    [3] - All PK analyses were based on the safety population in patients with evaluable samples.
    No statistical analyses for this end point

    Secondary: Everolimus steady state concentrations at predose (Cmin) and Cmax by region Asia vs. rest of world

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    End point title
    Everolimus steady state concentrations at predose (Cmin) and Cmax by region Asia vs. rest of world
    End point description
    Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.
    End point type
    Secondary
    End point timeframe
    Week 5
    End point values
    Everolimus + BSC Placebo + BSC
    Number of subjects analysed
    218 [4]
    18 [5]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Asia: Pre-dose (n:127, 11)
    16.804 ± 9.6163
    9.921 ± 5.1565
        Asia: Cmax (n:132, 10)
    73.568 ± 34.1898
    34.58 ± 26.811
        Rest of World: Pre-dose (n=74, 7)
    15.009 ± 12.5
    11.406 ± 7.8128
        Rest of World: Cmax (n=86, 6)
    71.558 ± 40.0655
    41.75 ± 29.8074
    Notes
    [4] - All PK analyses were based on the safety population in patients with evaluable samples.
    [5] - All PK analyses were based on the safety population in patients with evaluable samples.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    RAD001 plus best supportive care
    Reporting group description
    RAD001 plus best supportive care

    Reporting group title
    Placebo plus best supportive care
    Reporting group description
    Placebo plus best supportive care

    Serious adverse events
    RAD001 plus best supportive care Placebo plus best supportive care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    210 / 437 (48.05%)
    89 / 215 (41.40%)
         number of deaths (all causes)
    88
    49
         number of deaths resulting from adverse events
    1
    2
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 437 (0.69%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pallor
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour perforation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 437 (2.75%)
    6 / 215 (2.79%)
         occurrences causally related to treatment / all
    4 / 12
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    8 / 437 (1.83%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    3 / 8
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    14 / 437 (3.20%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    4 / 16
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    10 / 437 (2.29%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    6 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent malfunction
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Expressive language disorder
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Colon injury
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic rupture
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal injury
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    9 / 437 (2.06%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 437 (0.46%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    9 / 437 (2.06%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 437 (0.46%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 437 (0.92%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 437 (3.43%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    5 / 15
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 437 (0.92%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Depressed level of consciousness
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 437 (0.23%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal compartment syndrome
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    2 / 437 (0.46%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    21 / 437 (4.81%)
    12 / 215 (5.58%)
         occurrences causally related to treatment / all
    6 / 22
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 437 (0.46%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal rigidity
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    9 / 437 (2.06%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastrointestinal bleeding
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 437 (1.37%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    3 / 437 (0.69%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    5 / 437 (1.14%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flatulence
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    2 / 437 (0.46%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric stenosis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    13 / 437 (2.97%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    5 / 14
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 437 (0.46%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    5 / 437 (1.14%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Internal hernia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    5 / 437 (1.14%)
    5 / 215 (2.33%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 437 (0.23%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 437 (2.06%)
    9 / 215 (4.19%)
         occurrences causally related to treatment / all
    3 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    2 / 437 (0.46%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal disorder
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 437 (0.00%)
    3 / 215 (1.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 437 (0.69%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 437 (0.46%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    14 / 437 (3.20%)
    10 / 215 (4.65%)
         occurrences causally related to treatment / all
    6 / 16
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 437 (0.23%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    2 / 437 (0.46%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    4 / 437 (0.92%)
    5 / 215 (2.33%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    5 / 437 (1.14%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    21 / 437 (4.81%)
    8 / 215 (3.72%)
         occurrences causally related to treatment / all
    6 / 21
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 437 (0.69%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding disorder
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid intake reduced
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 437 (2.75%)
    4 / 215 (1.86%)
         occurrences causally related to treatment / all
    4 / 12
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 437 (0.46%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    4 / 437 (0.92%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 437 (0.92%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 215 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    RAD001 plus best supportive care Placebo plus best supportive care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    416 / 437 (95.19%)
    193 / 215 (89.77%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    28 / 437 (6.41%)
    9 / 215 (4.19%)
         occurrences all number
    29
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    34 / 437 (7.78%)
    8 / 215 (3.72%)
         occurrences all number
    35
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    34 / 437 (7.78%)
    6 / 215 (2.79%)
         occurrences all number
    36
    7
    Weight decreased
         subjects affected / exposed
    87 / 437 (19.91%)
    19 / 215 (8.84%)
         occurrences all number
    92
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    50 / 437 (11.44%)
    17 / 215 (7.91%)
         occurrences all number
    57
    18
    Dyspnoea
         subjects affected / exposed
    54 / 437 (12.36%)
    21 / 215 (9.77%)
         occurrences all number
    59
    21
    Epistaxis
         subjects affected / exposed
    29 / 437 (6.64%)
    1 / 215 (0.47%)
         occurrences all number
    32
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    108 / 437 (24.71%)
    42 / 215 (19.53%)
         occurrences all number
    135
    47
    Leukopenia
         subjects affected / exposed
    30 / 437 (6.86%)
    3 / 215 (1.40%)
         occurrences all number
    38
    3
    Neutropenia
         subjects affected / exposed
    47 / 437 (10.76%)
    6 / 215 (2.79%)
         occurrences all number
    65
    6
    Thrombocytopenia
         subjects affected / exposed
    77 / 437 (17.62%)
    4 / 215 (1.86%)
         occurrences all number
    93
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 437 (5.03%)
    12 / 215 (5.58%)
         occurrences all number
    27
    12
    Dysgeusia
         subjects affected / exposed
    26 / 437 (5.95%)
    7 / 215 (3.26%)
         occurrences all number
    29
    8
    Headache
         subjects affected / exposed
    32 / 437 (7.32%)
    8 / 215 (3.72%)
         occurrences all number
    37
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    67 / 437 (15.33%)
    18 / 215 (8.37%)
         occurrences all number
    72
    19
    Fatigue
         subjects affected / exposed
    146 / 437 (33.41%)
    63 / 215 (29.30%)
         occurrences all number
    169
    68
    Oedema peripheral
         subjects affected / exposed
    49 / 437 (11.21%)
    21 / 215 (9.77%)
         occurrences all number
    53
    23
    Pyrexia
         subjects affected / exposed
    77 / 437 (17.62%)
    24 / 215 (11.16%)
         occurrences all number
    108
    35
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    51 / 437 (11.67%)
    22 / 215 (10.23%)
         occurrences all number
    57
    23
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    39 / 437 (8.92%)
    20 / 215 (9.30%)
         occurrences all number
    39
    21
    Abdominal pain
         subjects affected / exposed
    90 / 437 (20.59%)
    49 / 215 (22.79%)
         occurrences all number
    105
    51
    Abdominal pain upper
         subjects affected / exposed
    51 / 437 (11.67%)
    26 / 215 (12.09%)
         occurrences all number
    59
    30
    Constipation
         subjects affected / exposed
    92 / 437 (21.05%)
    41 / 215 (19.07%)
         occurrences all number
    101
    45
    Diarrhoea
         subjects affected / exposed
    112 / 437 (25.63%)
    33 / 215 (15.35%)
         occurrences all number
    159
    37
    Dyspepsia
         subjects affected / exposed
    22 / 437 (5.03%)
    8 / 215 (3.72%)
         occurrences all number
    24
    8
    Nausea
         subjects affected / exposed
    129 / 437 (29.52%)
    63 / 215 (29.30%)
         occurrences all number
    147
    76
    Stomatitis
         subjects affected / exposed
    173 / 437 (39.59%)
    22 / 215 (10.23%)
         occurrences all number
    241
    26
    Vomiting
         subjects affected / exposed
    98 / 437 (22.43%)
    54 / 215 (25.12%)
         occurrences all number
    125
    70
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    24 / 437 (5.49%)
    5 / 215 (2.33%)
         occurrences all number
    28
    5
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    23 / 437 (5.26%)
    7 / 215 (3.26%)
         occurrences all number
    27
    7
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    22 / 437 (5.03%)
    2 / 215 (0.93%)
         occurrences all number
    23
    2
    Pruritus
         subjects affected / exposed
    47 / 437 (10.76%)
    9 / 215 (4.19%)
         occurrences all number
    54
    9
    Rash
         subjects affected / exposed
    86 / 437 (19.68%)
    19 / 215 (8.84%)
         occurrences all number
    110
    21
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    46 / 437 (10.53%)
    16 / 215 (7.44%)
         occurrences all number
    52
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    202 / 437 (46.22%)
    76 / 215 (35.35%)
         occurrences all number
    235
    82
    Hyperglycaemia
         subjects affected / exposed
    31 / 437 (7.09%)
    6 / 215 (2.79%)
         occurrences all number
    40
    6
    Hypoalbuminaemia
         subjects affected / exposed
    25 / 437 (5.72%)
    12 / 215 (5.58%)
         occurrences all number
    26
    13
    Hypokalaemia
         subjects affected / exposed
    52 / 437 (11.90%)
    9 / 215 (4.19%)
         occurrences all number
    61
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2010
    Clarifications to GEJ tumor language added, removal of amylase and lipase levels as an inclusion criterion, permitting enrollment of patients with grade 2 neuropathy, adding exclusion for patients with prior malignancies, removal of pulmonary function testing at screening, amending the pulmonary exclusion criterion, patients who were enterally fed were not eligible, and patients qualified for the study based on local laboratory results. Guidance provided for identification of patients at risk for hepatitis B, that include providing prophylactic treatment to them prior to and throughout everolimus therapy, monitoring them for reactivation of HBV, and management of patients at risk of hepatitis C viral reactivation. Guidance provided for management of hyperglycemia and duration of use of adequate contraception after end of trial therapy. Guidance provided regarding use of CYP3A4 and/or PgP inducers and inhibitors as modified with the Internal Clinical Pharmacology Drug-drug interaction memo; language modified regarding the administration of everolimus after meals; planned IDMC outputs excluded PK data; instead to receive unblinded safety data by prior gastrectomy (y/n); added separate exploratory Cox model on the sub-set of distal gastric tumor patients.

    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.
    Four randomized patients, 2 patients each from the everolimus and placebo arms were excluded from the safety analyses as they did not receive any dose of study treatment. This study did not meet its primary objective.
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