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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects with Locally Advanced or Metastatic, Non-Squamous, Non–Small-Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    2010-022365-10
    Trial protocol
    HU   CZ   DE   ES   IT   SE   GB   DK   AT   BE  
    Global end of trial date
    06 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Mar 2018
    First version publication date
    20 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARQ197-A-U302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01244191
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Clinical Trial Information, Daiichi Sankyo Development Limited, +44 1753482800, info@dsd-eu.com
    Scientific contact
    Clinical Trial Information, Daiichi Sankyo Development Limited, +44 1753482800, info@dsd-eu.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate overall survival (OS) in the intent-to-treat (ITT) subject population defined by this protocol.
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Conference on Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s). Dose delays and/or reductions were permitted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jan 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 67
    Country: Number of subjects enrolled
    United States: 229
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Argentina: 14
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Brazil: 45
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Peru: 11
    Country: Number of subjects enrolled
    Poland: 78
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Spain: 79
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    France: 101
    Country: Number of subjects enrolled
    Germany: 93
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    Italy: 152
    Worldwide total number of subjects
    1048
    EEA total number of subjects
    599
    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)
    646
    From 65 to 84 years
    399
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Between Jan 2011 and July 2012, of the 1624 patients screened, 1048 were randomized to treatment and formed the Intent-to-treat (ITT) Population. Results of the interim analysis met the protocol-defined stopping criteria. Protocol amendment 4 allowed only the EGFR mutant subgroup to continue (indicated here as Period 2).

    Pre-assignment
    Screening details
    A total of 1624 subjects were screened for this study in 23 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Erlotinib plus tivantinib
    Arm description
    Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 tivantinib 120 mg tablets twice daily with meals (for a daily dose of 720 mg).
    Arm type
    Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single tablet once daily at least 1 hour before or at least 2 hours after food.

    Investigational medicinal product name
    Tivantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Three 120 mg tablets twice daily with meals, for a total daily dose of 720 mg.

    Arm title
    Erlotinib plus placebo
    Arm description
    Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 placebo tablets twice daily with meals.
    Arm type
    Placebo

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single tablet once daily at least 1 hour before or at least 2 hours after food.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Three tablets twice daily with meals.

    Number of subjects in period 1
    Erlotinib plus tivantinib Erlotinib plus placebo
    Started
    526
    522
    Treated - safety analysis set
    520
    517
    Completed
    46
    24
    Not completed
    480
    498
         Progressive disease
    295
    350
         Protocol deviation
    1
    2
         Death
    22
    29
         Adverse event, non-fatal
    65
    48
         Consent withdrawn by subject
    31
    23
         Missing or study terminated by sponsor
    12
    8
         Lost to follow-up
    -
    2
         Clinical disease progression
    54
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Erlotinib plus tivantinib
    Reporting group description
    Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 tivantinib 120 mg tablets twice daily with meals (for a daily dose of 720 mg).

    Reporting group title
    Erlotinib plus placebo
    Reporting group description
    Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 placebo tablets twice daily with meals.

    Reporting group values
    Erlotinib plus tivantinib Erlotinib plus placebo Total
    Number of subjects
    526 522 1048
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    320 326 646
        From 65-84 years
    204 195 399
        85 years and over
    2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.2 ± 10.10 61.1 ± 9.84 -
    Gender categorical
    Units: Subjects
        Female
    216 213 429
        Male
    310 309 619

    End points

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    End points reporting groups
    Reporting group title
    Erlotinib plus tivantinib
    Reporting group description
    Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 tivantinib 120 mg tablets twice daily with meals (for a daily dose of 720 mg).

    Reporting group title
    Erlotinib plus placebo
    Reporting group description
    Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 placebo tablets twice daily with meals.

    Primary: Overall survival (OS) in Original Intent-to-treat (ITT) Population

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    End point title
    Overall survival (OS) in Original Intent-to-treat (ITT) Population
    End point description
    Median length of time patients survived
    End point type
    Primary
    End point timeframe
    by study completion, within 5 years, 9 months
    End point values
    Erlotinib plus tivantinib Erlotinib plus placebo
    Number of subjects analysed
    526
    522
    Units: months
        median (confidence interval 95%)
    8.5 (7.1 to 9.3)
    7.8 (7.0 to 9.0)
    Statistical analysis title
    Original ITT - OS Analysis
    Comparison groups
    Erlotinib plus tivantinib v Erlotinib plus placebo
    Number of subjects included in analysis
    1048
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8086 [1]
    Method
    Logrank
    Confidence interval
    Notes
    [1] - p-value from the stratified log-rank test [adjusting for number of prior therapies, gender, and smoking history using the IXRS (Randomization) data set] provides an overall comparison of the OS survival curves.

    Secondary: Progression-Free Survival (PFS) in the Original ITT Population

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    End point title
    Progression-Free Survival (PFS) in the Original ITT Population
    End point description
    Kaplan-Meier estimates of the median PFS times for each treatment group
    End point type
    Secondary
    End point timeframe
    by study completion, within 5 years, 9 months
    End point values
    Erlotinib plus tivantinib Erlotinib plus placebo
    Number of subjects analysed
    526
    522
    Units: months
        median (confidence interval 95%)
    3.6 (2.8 to 3.7)
    1.9 (1.9 to 2.0)
    Statistical analysis title
    Period 1 Original ITT
    Comparison groups
    Erlotinib plus tivantinib v Erlotinib plus placebo
    Number of subjects included in analysis
    1048
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [2]
    Method
    Logrank
    Confidence interval
    Notes
    [2] - p-value from the stratified log-rank test (adjusting for number of prior therapies, gender, and smoking history using the IXRS data set) provides an overall comparison of the PFS survival curves

    Other pre-specified: Overall Survival in the EGFR Mutant Subpopulation (ITT)

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    End point title
    Overall Survival in the EGFR Mutant Subpopulation (ITT)
    End point description
    Median length of time patients survived who were in the EGFR-mutant sub-population that continued until November 2014
    End point type
    Other pre-specified
    End point timeframe
    by study completion, within 5 years, 9 months
    End point values
    Erlotinib plus tivantinib Erlotinib plus placebo
    Number of subjects analysed
    56
    53
    Units: months
        median (confidence interval 95%)
    25.5 (15.6 to 38.9)
    20.3 (16.6 to 24.3)
    Statistical analysis title
    EGFR-Mutant Analysis
    Statistical analysis description
    Analysis of EGFR-mutant patients who continued during Amended Protocol 4
    Comparison groups
    Erlotinib plus tivantinib v Erlotinib plus placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1013 [3]
    Method
    Logrank
    Confidence interval
    Notes
    [3] - p-value from the stratified log-rank test (adjusting for number of prior therapies, gender, and smoking history) provides an overall comparison of the PFS survival curves

    Other pre-specified: Progression-Free Survival in the EGFR Mutant Subpopulation (ITT)

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    End point title
    Progression-Free Survival in the EGFR Mutant Subpopulation (ITT)
    End point description
    Kaplan-Meier estimates of the median PFS times for each treatment group
    End point type
    Other pre-specified
    End point timeframe
    by study completion, within 5 years, 9 months
    End point values
    Erlotinib plus tivantinib Erlotinib plus placebo
    Number of subjects analysed
    56
    53
    Units: months
        median (confidence interval 95%)
    13.0 (7.3 to 17.7)
    7.5 (5.6 to 11.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were collected until 30 days after completing treatment, within 5 years, 9 months. TEAEs that occurred more than 30 days after the last dose of study medication are not included unless related to treatment.
    Adverse event reporting additional description
    At each level of summarizing TEAEs, a patient was counted only once if he/she reported one or more adverse events in this older trial. Therefore, the number of events mirrors the number of patients. Relatedness is based on the experimental products placebo and tivantinib only.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Erlotinib plus placebo
    Reporting group description
    -

    Reporting group title
    Erlotinib plus tivantinib
    Reporting group description
    -

    Serious adverse events
    Erlotinib plus placebo Erlotinib plus tivantinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    198 / 517 (38.30%)
    228 / 520 (43.85%)
         number of deaths (all causes)
    300
    314
         number of deaths resulting from adverse events
    67
    82
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (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
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Superior vena caval occlusion
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous insufficiency
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         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
    4 / 517 (0.77%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spleen
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Paraneoplastic syndrome
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord neoplasm
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    1 / 517 (0.19%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 517 (0.97%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 517 (0.39%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    13 / 517 (2.51%)
    16 / 520 (3.08%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 16
         deaths causally related to treatment / all
    0 / 7
    0 / 10
    Malaise
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 517 (0.58%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Performance status decreased
         subjects affected / exposed
    3 / 517 (0.58%)
    5 / 520 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Pyrexia
         subjects affected / exposed
    5 / 517 (0.97%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder due to a general medical condition
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Collapse of lung
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug toxicity
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulation test abnormal
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 517 (0.19%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchospasm
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 517 (0.77%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse alveolar damage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    24 / 517 (4.64%)
    28 / 520 (5.38%)
         occurrences causally related to treatment / all
    2 / 24
    0 / 28
         deaths causally related to treatment / all
    0 / 8
    0 / 11
    Dyspnoea exertional
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 517 (0.77%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Hypoxia
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Lung disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    9 / 517 (1.74%)
    13 / 520 (2.50%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleurisy
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 517 (0.00%)
    5 / 520 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Productive cough
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    20 / 517 (3.87%)
    17 / 520 (3.27%)
         occurrences causally related to treatment / all
    4 / 20
    2 / 17
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    9 / 517 (1.74%)
    12 / 520 (2.31%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 12
         deaths causally related to treatment / all
    0 / 8
    1 / 8
    Tracheal stenosis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 517 (1.35%)
    16 / 520 (3.08%)
         occurrences causally related to treatment / all
    2 / 7
    11 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 517 (0.39%)
    15 / 520 (2.88%)
         occurrences causally related to treatment / all
    0 / 2
    11 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Lymphadenopathy
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 517 (0.19%)
    12 / 520 (2.31%)
         occurrences causally related to treatment / all
    0 / 1
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pancytopenia
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 517 (0.00%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain compression
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 517 (0.77%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Coma
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    5 / 517 (0.97%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Demyelination
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiduritis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 517 (0.19%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain lower
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 517 (0.00%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 517 (1.35%)
    4 / 520 (0.77%)
         occurrences causally related to treatment / all
    2 / 7
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric ulcer
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal infarction
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 517 (0.39%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (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
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    6 / 517 (1.16%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal disorder
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         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 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    5 / 517 (0.97%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (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 / 517 (0.39%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         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 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Nail toxicity
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous nodule
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (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
    3 / 517 (0.58%)
    5 / 520 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bone pain
         subjects affected / exposed
    2 / 517 (0.39%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 517 (0.58%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (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 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 517 (1.35%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 517 (0.77%)
    5 / 520 (0.96%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypercalcaemia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 517 (0.00%)
    2 / 520 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    5 / 517 (0.97%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    2 / 517 (0.39%)
    3 / 520 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cystitis
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 517 (0.77%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Perirectal abscess
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 517 (2.51%)
    22 / 520 (4.23%)
         occurrences causally related to treatment / all
    1 / 13
    2 / 22
         deaths causally related to treatment / all
    1 / 3
    1 / 3
    Pyelonephritis acute
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyothorax
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 517 (0.39%)
    6 / 520 (1.15%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Septic shock
         subjects affected / exposed
    1 / 517 (0.19%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 517 (0.00%)
    1 / 520 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 517 (0.58%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 517 (0.19%)
    0 / 520 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Erlotinib plus placebo Erlotinib plus tivantinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    496 / 517 (95.94%)
    505 / 520 (97.12%)
    Investigations
    Weight decreased
         subjects affected / exposed
    59 / 517 (11.41%)
    59 / 520 (11.35%)
         occurrences all number
    59
    59
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    48 / 517 (9.28%)
    78 / 520 (15.00%)
         occurrences all number
    48
    78
    Neutropenia
         subjects affected / exposed
    11 / 517 (2.13%)
    57 / 520 (10.96%)
         occurrences all number
    11
    57
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    102 / 517 (19.73%)
    128 / 520 (24.62%)
         occurrences all number
    102
    128
    Cough
         subjects affected / exposed
    95 / 517 (18.38%)
    115 / 520 (22.12%)
         occurrences all number
    95
    115
    Haemoptysis
         subjects affected / exposed
    15 / 517 (2.90%)
    30 / 520 (5.77%)
         occurrences all number
    15
    30
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 517 (5.61%)
    43 / 520 (8.27%)
         occurrences all number
    29
    43
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    113 / 517 (21.86%)
    139 / 520 (26.73%)
         occurrences all number
    113
    139
    Asthenia
         subjects affected / exposed
    91 / 517 (17.60%)
    101 / 520 (19.42%)
         occurrences all number
    91
    101
    Pyrexia
         subjects affected / exposed
    41 / 517 (7.93%)
    62 / 520 (11.92%)
         occurrences all number
    41
    62
    Oedema peripheral
         subjects affected / exposed
    30 / 517 (5.80%)
    40 / 520 (7.69%)
         occurrences all number
    30
    40
    Non-cardiac chest pain
         subjects affected / exposed
    23 / 517 (4.45%)
    35 / 520 (6.73%)
         occurrences all number
    23
    35
    Mucosal inflammation
         subjects affected / exposed
    24 / 517 (4.64%)
    29 / 520 (5.58%)
         occurrences all number
    24
    29
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 517 (5.61%)
    34 / 520 (6.54%)
         occurrences all number
    29
    34
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    215 / 517 (41.59%)
    181 / 520 (34.81%)
         occurrences all number
    215
    181
    Nausea
         subjects affected / exposed
    123 / 517 (23.79%)
    123 / 520 (23.65%)
         occurrences all number
    123
    123
    Vomiting
         subjects affected / exposed
    81 / 517 (15.67%)
    77 / 520 (14.81%)
         occurrences all number
    81
    77
    Constipation
         subjects affected / exposed
    54 / 517 (10.44%)
    58 / 520 (11.15%)
         occurrences all number
    54
    58
    Abdominal pain
         subjects affected / exposed
    26 / 517 (5.03%)
    35 / 520 (6.73%)
         occurrences all number
    26
    35
    Dyspepsia
         subjects affected / exposed
    24 / 517 (4.64%)
    31 / 520 (5.96%)
         occurrences all number
    24
    31
    Abdominal pain upper
         subjects affected / exposed
    19 / 517 (3.68%)
    33 / 520 (6.35%)
         occurrences all number
    19
    33
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    193 / 517 (37.33%)
    173 / 520 (33.27%)
         occurrences all number
    193
    173
    Dermatitis acneiform
         subjects affected / exposed
    98 / 517 (18.96%)
    91 / 520 (17.50%)
         occurrences all number
    98
    91
    Dry skin
         subjects affected / exposed
    57 / 517 (11.03%)
    42 / 520 (8.08%)
         occurrences all number
    57
    42
    Pruritus
         subjects affected / exposed
    45 / 517 (8.70%)
    32 / 520 (6.15%)
         occurrences all number
    45
    32
    Alopecia
         subjects affected / exposed
    14 / 517 (2.71%)
    27 / 520 (5.19%)
         occurrences all number
    14
    27
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    47 / 517 (9.09%)
    55 / 520 (10.58%)
         occurrences all number
    47
    55
    Pain in extremity
         subjects affected / exposed
    19 / 517 (3.68%)
    31 / 520 (5.96%)
         occurrences all number
    19
    31
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    149 / 517 (28.82%)
    152 / 520 (29.23%)
         occurrences all number
    149
    152

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2010
    - Revised to require prior platinum-doublet therapy, and clarify eligibility requirements for subjects with prior adjuvant or maintenance therapy - Specified that subjects who experienced ≥ Grade 3 neutropenia were to be monitored closely throughout study and offered hematopoietic growth factor therapy as per ASCO guidelines. Also, increased frequency of ANC monitoring for Cycles 3+ from every 4 weeks to every 2 weeks for all subjects, not only those receiving CYP 2C19 or CYP 3A4 inhibitors. - Added precaution for potential of concomitant medications altering gastric pH to affect erlotinib absorption - Added fluconazole, ticlopidine, rabeprazole, and fluoxetine to list of example CYP 2C19 inhibitors to be used with caution concomitantly - Clarified that AEs recorded at Screening visit were to include only those AEs occurring after consent was signed - Removed qualification “if not restricted by local regulation” to require collection of pharmacogenomic data at all sites - Modified language to specify that hematology testing would be performed for all subjects every 2 weeks rather than every 4 weeks in Cycle 3 and beyond - Removed limit of precaution to only “strong” CYP 2C19 inhibitors, but clarified limit to precaution for only strong inhibitors of CYP 3A4 - Specified requirement for biomarker testing for tumor MET, EGFR, and KRAS for all subjects, as well as testing for pre- and posttreatment circulating HGF - Added language specifying data sets and analyses for pharmacogenomic data and PK–pharmacodynamic analyses
    01 Jun 2011
    - Added exception for enrollment of subjects with ≤ Grade 2 neuropathy - Reduced window for prior surgical procedure, prior systemic anti-tumor therapy, and prior radiotherapy from 4 weeks to 3 weeks - Clarified description of exploratory objectives, endpoints, and analyses with regard to MET status as determined by IHC and FISH. Specifically, the exploratory analysis for evaluating OS and PFS by MET/MET was to be performed using both IHC and FISH analytical methods instead of FISH method only. - Clarified that either archival or fresh tissue biopsy samples would qualify for study eligibility; documented EGFR and KRAS status must have been from an accredited lab; specified that tissue must be provided to central laboratories for MET analysis even if EGFR, KRAS results were obtained locally - Noted that EGFR status was required for study eligibility; in the absence of confirmation of a subject’s KRAS status, the subject was to be categorized as “indeterminate” for KRAS - Added exception to the prohibition of highdose corticosteroids for short-term treatment of COPD or other inflammation exacerbation
    28 Nov 2012
    - Revised text to indicate that only subjects with EGFR-mutant disease would be included in survival followup evaluations - Revised text to indicate that study closure was to be defined as the final subject visit/contact rather than when the pre-specified 735 deaths have occurred The interim results for this study met the protocol-defined stopping boundary for futility based on overall survival (OS). After reviewing the interim analysis, the data management committee (DMC) concluded that the study would not meet its primary endpoint of improved OS in the intent to treat (ITT) population, and therefore recommended that the study be stopped early. However, the DMC noted that there was no unexpected safety concern requiring immediate treatment discontinuation, and there was a trend toward improvement in progression free survival (PFS) in the ITT population at the interim analysis. Based upon this result, the data were cut on 15 Dec 2012 for the main study analyses included in the original CSR. Patients receiving clinical benefit were allowed to continue. At the time of the data-cut for the main study analyses, the results for EGFR mutant subgroup, which responds well to erlotinib therapy, were not mature. The clinical trial protocol was amended to allow these subjects to continue with follow-up assessments in order to provide mature results for this subgroup. The results posted herein incorporate the tables, figures, and listings for the pre-specified data-cut (Nov 2014) for the EGFR mutant subgroup. This clinical study has now been completed and the full database is locked. This record also includes the isolated EGFR mutant data that were collected during the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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