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    Clinical Trial Results:
    Open Label, Multinational, Multicenter, Real-World Treatment Study of Single Agent AZD9291 for Patients with Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Prior Therapy with an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI)

    Summary
    EudraCT number
    		 2015-001407-31
    Trial protocol
    		 SE   BE   IT   AT   DK   ES   IE  
    Global end of trial date
    18 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2021
    First version publication date
    28 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5160C00022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02474355
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.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
    10 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 30
    Country: Number of subjects enrolled
    Australia: 31
    Country: Number of subjects enrolled
    Austria: 46
    Country: Number of subjects enrolled
    Belgium: 31
    Country: Number of subjects enrolled
    Brazil: 88
    Country: Number of subjects enrolled
    Canada: 99
    Country: Number of subjects enrolled
    China: 1350
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Italy: 510
    Country: Number of subjects enrolled
    Saudi Arabia: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 466
    Country: Number of subjects enrolled
    Spain: 131
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Taiwan: 188
    Country: Number of subjects enrolled
    United Kingdom: 18
    Worldwide total number of subjects
    3014
    EEA total number of subjects
    741
    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)
    1798
    From 65 to 84 years
    1185
    85 years and over
    31

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants who met all the inclusion and none of the exclusion criteria received treatment in a total of 209 centres in 16 countries. The study started on 18 September 2015 and primary completion date was 18 April 2019.

    Pre-assignment
    Screening details
    		 During the screening period (28 days), eligible participants signed the informed consent. All the study assessments were performed as per the schedule of assessment.

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

    Arms
    Arm title
    		 Osimertinib
    Arm description
    		 All participants received oral 80 mg tablet once a day (the dose could be reduced to 40 mg for management of osimertinib-related toxicities)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Osimertinib
    Investigational medicinal product code
    Other name
    AZD9291
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received oral 80 mg tablet once a day (the dose could be reduced to 40 mg for management of osimertinib-related toxicities).

    Number of subjects in period 1
    		Osimertinib
    Started
    3014
    Completed
    1386
    Not completed
    1628
         Consent withdrawn by subject
    124
         Eligibility Criteria not Fulfilled
    2
         Other
    43
         Death
    1361
         Lost to follow-up
    98

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Osimertinib
    Reporting group description
    		 All participants received oral 80 mg tablet once a day (the dose could be reduced to 40 mg for management of osimertinib-related toxicities)

    Reporting group values
    		 Osimertinib Total
    Number of subjects
    		 3014 3014
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0
        Between 18 and 65 years
    		 1798 1798
        >=65 years
    		 1216 1216
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.7 ( 10.91 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 1927 1927
        Male
    		 1087 1087
    Country
    Units: Subjects
        Argentina
    		 30 30
        Australia
    		 31 31
        Austria
    		 46 46
        Belgium
    		 31 31
        Brazil
    		 88 88
        Canada
    		 99 99
        China
    		 1350 1350
        Denmark
    		 6 6
        Ireland
    		 10 10
        Italy
    		 510 510
        Saudi Arabia
    		 3 3
        South Korea
    		 466 466
        Spain
    		 131 131
        Sweden
    		 7 7
        Taiwan
    		 188 188
        United Kingdom
    		 18 18
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 2085 2085
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 21 21
        White
    		 897 897
        More than one race
    		 0 0
        Unknown or Not Reported
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    Osimertinib
    Reporting group description
    		 All participants received oral 80 mg tablet once a day (the dose could be reduced to 40 mg for management of osimertinib-related toxicities)

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [1]
    End point description
    OS was defined as the time, in months from the date of first dose of Osimertinib until death due to any cause, or at last documented contact with participant status “alive” (in this study any participants alive at study discontinuation, or lost to follow-up was considered being censored at study discontinuation date or at the last known date participant was alive). OS was summarized using a Kaplan-Meier (KM) estimate of the median time to death or censoring together with their 95% confidence intervals.
    End point type
    Primary
    End point timeframe
    From the date of first dose of Osimertinib until the date of death (due to any cause) or last participant contact [up to 43 months]
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical tests were performed, the statistical analyses were descriptive.
    End point values
    		 Osimertinib
    Number of subjects analysed
    3014
    Units: Months
        median (confidence interval 95%)
    22.8 (21.6 to 23.8)
    No statistical analyses for this end point

    Primary: Number of participants with serious adverse events (SAEs), AEs leading to dose modification, AEs leading to discontinuation, AEs of special interest (AESIs)

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    End point title
    		 Number of participants with serious adverse events (SAEs), AEs leading to dose modification, AEs leading to discontinuation, AEs of special interest (AESIs) [2]
    End point description
    Safety assessment of Osimertinib was analyzed by evaluating SAEs, AEs leading to dose modification, AEs leading to discontinuation, AESIs.
    End point type
    Primary
    End point timeframe
    From screening to progession follow-up [every 6 weeks (± 1 week) relative to the date of enrolment until end of study]
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical tests were performed, the statistical analyses were descriptive.
    End point values
    		 Osimertinib
    Number of subjects analysed
    3014
    Units: Participants
        AE of special interest (AESI) or SAE
    923
        AESI or SAE a causally related to Osimertinib
    338
        AE leading to dose modification
    414
        AE leading to discontinuation
    191
        AESI
    113
        AESI causally related to Osimertinib
    89
        SAE
    657
        SAE causally related to Osimertinib
    95
        AE leading to death
    152
        AE leading to death related to Osimertinib
    19
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    PFS was defined as the time, in months from first dose of Osimertinib until the date of disease progression or death in the absence of progression. Participants who had not progressed or died at study discontinuation were censored at the time of the latest date of disease assessment. PFS was summarized using KM estimates of the median time to progression or death with their 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months]
    End point values
    		 Osimertinib
    Number of subjects analysed
    3014
    Units: Months
        median (confidence interval 95%)
    11.1 (11.0 to 12.0)
    No statistical analyses for this end point

    Secondary: Time to Treatment Discontinuation (TTD)

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    End point title
    		 Time to Treatment Discontinuation (TTD)
    End point description
    TTD or death was assessed as a supportive summary to PFS and defined as the time from the date of the first dose of osimertinib in the study until the date of osimertinib discontinuation or death, regardless of the reason for discontinuation. TTD was summarized using KM estimates of the median times to progression or death or treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months]
    End point values
    		 Osimertinib
    Number of subjects analysed
    3014
    Units: Months
        median (confidence interval 95%)
    13.5 (12.6 to 13.9)
    No statistical analyses for this end point

    Secondary: Response rate (RR)

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    End point title
    		 Response rate (RR)
    End point description
    RR was defined as the number (%) of participants with a best response (by Investigator assessment) of ‘responding’, regardless of the method of evaluation, and was based on a subset of the full analysis set consisting of subjects with at least one documented response assessment. RR was summarised together with the 95% CI.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of Osimertinib until disease progression or death in the absence of progression [up to 43 months]
    End point values
    		 Osimertinib
    Number of subjects analysed
    3014
    Units: Percentage
        number (confidence interval 95%)
    57.3 (55.5 to 59.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening to progession follow-up [every 6 weeks (± 1 week) relative to the date of enrolment until end of study]
    Adverse event reporting additional description
    Safety of AZD9291 by assessment of SAEs, AEs of special interest (AESI) [Interstitial Lung Disease/pneumonitis-like events, and QTc prolongation events]. This study did not collect all AEs; only SAEs, adverse events leading to dose modification, adverse events leading to treatment discontinuation and AESI were collected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Osimertinib
    Reporting group description
    		 All participants received oral 80 mg tablet once a day (the dose could be reduced to 40 mg for management of osimertinib-related toxicities).

    Serious adverse events
    		 Osimertinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    657 / 3014 (21.80%)
         number of deaths (all causes)
    1361
         number of deaths resulting from adverse events
    19
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute promyelocytic leukaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Breast cancer female
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Uterine leiomyoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    17 / 3014 (0.56%)
         occurrences causally related to treatment / all
    2 / 18
         deaths causally related to treatment / all
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Unintended pregnancy
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    34 / 3014 (1.13%)
         occurrences causally related to treatment / all
    1 / 34
         deaths causally related to treatment / all
    1 / 34
    Asthenia
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    12 / 3014 (0.40%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Gait disturbance
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Chest discomfort
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Granuloma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    49 / 3014 (1.63%)
         occurrences causally related to treatment / all
    5 / 49
         deaths causally related to treatment / all
    3 / 13
    Pleural effusion
         subjects affected / exposed
    20 / 3014 (0.66%)
         occurrences causally related to treatment / all
    1 / 25
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    15 / 3014 (0.50%)
         occurrences causally related to treatment / all
    2 / 15
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    11 / 3014 (0.36%)
         occurrences causally related to treatment / all
    2 / 11
         deaths causally related to treatment / all
    2 / 9
    Interstitial lung disease
         subjects affected / exposed
    9 / 3014 (0.30%)
         occurrences causally related to treatment / all
    7 / 9
         deaths causally related to treatment / all
    3 / 4
    Pneumonitis
         subjects affected / exposed
    9 / 3014 (0.30%)
         occurrences causally related to treatment / all
    6 / 9
         deaths causally related to treatment / all
    0 / 1
    Asphyxia
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    Pneumothorax
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Bronchitis chronic
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute interstitial pneumonitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Asthma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Delirium
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Breath holding
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Amylase increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza A virus test
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    8 / 3014 (0.27%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Multiple injuries
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain herniation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Compression fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foreign body in respiratory tract
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulnar nerve injury
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    9 / 3014 (0.30%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    1 / 3
    Cardiac arrest
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 5
    Myocardial infarction
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Arrhythmia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac dysfunction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiotoxicity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypertensive heart disease
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    22 / 3014 (0.73%)
         occurrences causally related to treatment / all
    5 / 22
         deaths causally related to treatment / all
    2 / 11
    Headache
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    Epilepsy
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Lacunar infarction
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Apraxia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal ganglia infarction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebellar ischaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychomotor skills impaired
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular headache
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Myelosuppression
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone marrow disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Middle ear inflammation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertigo
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dacryostenosis acquired
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    13 / 3014 (0.43%)
         occurrences causally related to treatment / all
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 3014 (0.40%)
         occurrences causally related to treatment / all
    6 / 12
         deaths causally related to treatment / all
    1 / 1
    Nausea
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    7 / 3014 (0.23%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Pancreatitis acute
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastric perforation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gingival ulceration
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ischaemic enteritis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Biliary colic
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    Renal failure
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Haematuria
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 3014 (0.23%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Arthralgia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant psoas syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertebral lesion
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    74 / 3014 (2.46%)
         occurrences causally related to treatment / all
    7 / 79
         deaths causally related to treatment / all
    4 / 20
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 3014 (0.33%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    10 / 3014 (0.33%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    7 / 3014 (0.23%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Device related infection
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Empyema
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Complicated appendicitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic fever
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterobacter pneumonia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective spondylitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucosal infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasal abscess
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral nerve infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scrub typhus
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    8 / 3014 (0.27%)
         occurrences causally related to treatment / all
    2 / 11
         deaths causally related to treatment / all
    0 / 1
    Decreased appetite
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    Cachexia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Hyperglycaemia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Osimertinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    380 / 3014 (12.61%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Haematoma
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 3014 (0.23%)
         occurrences all number
    7
    Asthenia
         subjects affected / exposed
    8 / 3014 (0.27%)
         occurrences all number
    8
    Fatigue
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences all number
    5
    General physical health deterioration
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences all number
    4
    Inflammation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Testicular cyst
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    13 / 3014 (0.43%)
         occurrences all number
    14
    Cough
         subjects affected / exposed
    4 / 3014 (0.13%)
         occurrences all number
    4
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Interstitial lung disease
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    3
    Haemoptysis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Organising pneumonia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Pulmonary toxicity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 3014 (0.33%)
         occurrences all number
    11
    Platelet count decreased
         subjects affected / exposed
    17 / 3014 (0.56%)
         occurrences all number
    25
    Electrocardiogram QT prolonged
         subjects affected / exposed
    88 / 3014 (2.92%)
         occurrences all number
    122
    Blood creatinine increased
         subjects affected / exposed
    10 / 3014 (0.33%)
         occurrences all number
    14
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 3014 (0.30%)
         occurrences all number
    10
    Neutrophil count decreased
         subjects affected / exposed
    9 / 3014 (0.30%)
         occurrences all number
    12
    White blood cell count decreased
         subjects affected / exposed
    8 / 3014 (0.27%)
         occurrences all number
    8
    Amylase increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Lipase increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    3
    Transaminases increased
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Chemical burns of eye
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Corneal abrasion
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Extrasystoles
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Cardiac failure
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Bundle branch block left
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Nodal rhythm
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences all number
    3
    Presyncope
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Balance disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Brain oedema
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Cognitive disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Demyelination
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Facial nerve disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Nervous system disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Sciatica
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Psychomotor skills impaired
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Seizure
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    20 / 3014 (0.66%)
         occurrences all number
    22
    Neutropenia
         subjects affected / exposed
    16 / 3014 (0.53%)
         occurrences all number
    24
    Myelosuppression
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences all number
    8
    Anaemia
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences all number
    6
    Leukopenia
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences all number
    4
    Pancytopenia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Blepharitis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Ulcerative keratitis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Swelling of eyelid
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Visual acuity reduced
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Vitreoretinal traction syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 3014 (0.36%)
         occurrences all number
    12
    Diarrhoea
         subjects affected / exposed
    30 / 3014 (1.00%)
         occurrences all number
    37
    Vomiting
         subjects affected / exposed
    10 / 3014 (0.33%)
         occurrences all number
    14
    Stomatitis
         subjects affected / exposed
    9 / 3014 (0.30%)
         occurrences all number
    10
    Abdominal pain upper
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Dysphagia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Anal inflammation
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Lip swelling
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences all number
    3
    Drug-induced liver injury
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hepatotoxicity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    2
    Liver injury
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    10 / 3014 (0.33%)
         occurrences all number
    11
    Dermatitis acneiform
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences all number
    6
    Skin toxicity
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences all number
    7
    Pruritus
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences all number
    4
    Nail disorder
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Dry skin
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Drug eruption
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Eczema asteatotic
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Onycholysis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Rash papular
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Skin fissures
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Skin reaction
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Renal impairment
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Acute kidney injury
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hydronephrosis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    2
    Nephropathy toxic
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Renal disorder
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Hypercreatinaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Arthralgia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Spinal pain
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Pathological fracture
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    7 / 3014 (0.23%)
         occurrences all number
    9
    Paronychia
         subjects affected / exposed
    11 / 3014 (0.36%)
         occurrences all number
    11
    Herpes zoster
         subjects affected / exposed
    6 / 3014 (0.20%)
         occurrences all number
    6
    Pneumonia
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences all number
    5
    Atypical pneumonia
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Cystitis
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Gastroenteritis viral
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Herpes ophthalmic
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Pneumonia viral
         subjects affected / exposed
    2 / 3014 (0.07%)
         occurrences all number
    2
    Bronchitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Gingivitis
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 3014 (0.17%)
         occurrences all number
    5
    Hyponatraemia
         subjects affected / exposed
    3 / 3014 (0.10%)
         occurrences all number
    3
    Dehydration
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Abnormal loss of weight
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 3014 (0.03%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2015
    - Patient recruitment was expanded to other regions (America and Asia), a clause about study termination in each country was added and procedures for discontinuation of a subject from study treatment were added, details about what will happen in case of study withdrawal and follow up of overall survival were added, the study plan (Table 4) was amended to provide more details in line with the CRF and more details about the enrolment process, clarification about T790M testing and what will happen to the samples if a central laboratory is used. - Male patient contraception was clarified. - Details regarding QTc prolongation and identity and dose of investigational product were aligned to the core data sheet. - The statistical methods and analysis included a more robust description of statistical evaluations and sample size determination.
    23 Jun 2016
    - The number of patients enrolled was revised in Europe from 1500 to 600 due to lower enrolment than initially planned. The total enrolment was more defined as approximately 3500 with the participation of China. - The data collection is to stop at last patient last visit due to the removal of the patient registry after national reimbursement. - The primary efficacy outcome was clarified as overall survival, the secondary efficacy outcomes were clarified as investigator assessed response rate, investigator assessed progression free survival and time to treatment discontinuation. - Definition for response rate and time to treatment discontinuation was added. - The exclusion criteria relating to patients being excluded due to evidence of an active infection was clarified with a definition for active infection. - An interim analysis of the global data was added to take place annually for the first 3 years. - A steering committee was added for oversight and supervision of the study.
    20 Oct 2016
    - Details were added regarding an addendum to the informed consent form to be signed and dated to enable the collection of images (CT scans or MRI) from a selected subset of patients for independent central analysis by an AstraZeneca appointed CRO. - Table 4 (footnote c) was amended to clarify the 30 days post last follow up contact is by a visit or by telephone (for new/ongoing serious adverse events (SAEs) and adverse events of special interest. - Details regarding definition and management of overdose were added and it was clarified that all overdose data (not just those relating to an SAE) should be reported to AstraZeneca with details of the process.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Aug 2018
    Delay to database lock due to needing a further approval to consent patients and collect scans in one of the participating countries.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Participants alive at the time of national reimbursement or site closure were no longer followed for survival and therefore prematurely censored for the OS, PFS, and TTD analysis, leading to less mature data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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