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    Clinical Trial Results:
    Phase III study comparing maintenance by pemetrexed or gemcitabine to surveillance in elderly patient (≥ 70 year old) with advanced Non Small Cell Lung Cancer controlled by induction chemotherapy

    Summary
    EudraCT number
    		 2012-005520-15
    Trial protocol
    		 FR  
    Global end of trial date
    31 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jan 2023
    First version publication date
    26 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IFCT-1201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01850303
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IFCT
    Sponsor organisation address
    10 Rue de la Grange Batelière , Paris, France, 75009
    Public contact
    Contact, IFCT, 33 1.56.81.10.46, contact@ifct.fr
    Scientific contact
    Contact, IFCT, 33 1.56.81.10.46, contact@ifct.fr
    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
    01 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Overall survival of patients whose disease is controlled after induction chemotherapy with 4 cycles of carboplatin and paclitaxel weekly from randomization maintenance versus observation.
    Protection of trial subjects
    Algorithms for management of adverse events were provided in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 627
    Worldwide total number of subjects
    627
    EEA total number of subjects
    627
    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)
    0
    From 65 to 84 years
    601
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    		 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine.

    Pre-assignment
    Screening details
    		 Patients should have a histologically/cytologically confirmed stage IV or III not amenable to surgery or radiotherapy NSCLC, an age between 70 and 89 years, a performance status (PS) 0-2, a mini-mental score (MMS) > 23/30 and appropriate hepatic and renal functions and haematopoietic reserves.

    Period 1
    Period 1 title
    Induction
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Paclitaxel - Carboplatin
    Arm description
    		 -
    Arm type
    		 Induction

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel IV 90 mg/m² at D1, D8, D15 ; cycles repeated every 28 days.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin IV AUC6 (D1= D29); cycles repeated every 28 days.

    Number of subjects in period 1
    		Paclitaxel - Carboplatin
    Started
    627
    Completed
    328
    Not completed
    299
         Consent withdrawn by subject
    19
         Physician decision
    2
         Adverse event, non-fatal
    39
         Death
    53
         Not specified
    11
         Performans status >2
    12
         Treatment not received
    4
         Lack of efficacy
    159
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm A - Follow-up
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm B1 - Maintenance Pemetrexed
    Arm description
    		 Pemetrexed for patients with non-squamous cell carcinoma
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Maintenance switch with pemetrexed IV 500 mg/m2 every 3 weeks until progression or toxicity.

    Arm title
    		 ARM B2 - Maintenance Gemcitabine
    Arm description
    		 Gemcitabine for patients with squamous cell carcinoma
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Maintenance switch with gemcitabine monotherapy IV (1150 mg/m² on Day 1, Day 8, cycles repeated every 21 days) until progression or unacceptable toxicity

    Arm title
    		 ARM B - Maintenance
    Arm description
    		 Pemetrexed for patients with non-squamous cell carcinoma Gemcitabine for patients with squamous cell carcinoma
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Maintenance switch with pemetrexed IV 500 mg/m2 every 3 weeks until progression or toxicity.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Maintenance switch with gemcitabine monotherapy IV (1150 mg/m² on Day 1, Day 8, cycles repeated every 21 days) until progression or unacceptable toxicity

    Number of subjects in period 2
    		Arm A - Follow-up Arm B1 - Maintenance Pemetrexed ARM B2 - Maintenance Gemcitabine ARM B - Maintenance
    Started
    166
    119
    43
    162
    Completed
    166
    109
    43
    152
    Not completed
    0
    10
    0
    10
         Not received treatment
    -
    -
    -
    10
         Not received Pemetrexed
    -
    10
    -
    -
    Period 3
    Period 3 title
    Second line Erlotinib
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Erlotinib
    Arm description
    		 Second line fixed with erlotinib in case of disease progression (RECIST 1.1).
    Arm type
    		 Second line fixed with erlotinib

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib 150 mg/day

    Number of subjects in period 3
    		Erlotinib
    Started
    173
    Completed
    173

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction
    Reporting group description
    		 -

    Reporting group values
    		 Induction Total
    Number of subjects
    		 627 627
    Age categorical
    Units: Subjects
        From 70 to 79
    		 486 486
        From 80 to 89
    		 141 141
    Age continuous
    Units: years
        median (full range (min-max))
    		 76.4 (70.0 to 89.4) -
    Gender categorical
    Units: Subjects
        Female
    		 152 152
        Male
    		 475 475
    Performans status (PS)
    Units: Subjects
        PS 0-1
    		 535 535
        PS 2
    		 86 86
        Not evaluated
    		 6 6
    Stage
    Units: Subjects
        Stage III
    		 62 62
        Stage IV
    		 565 565
    Smocking status
    Units: Subjects
        Smoker
    		 535 535
        Never Smocker
    		 92 92
    Histology subtype
    Units: Subjects
        Adenocarcinoma
    		 401 401
        Squamous cell
    		 178 178
        Large Cell
    		 13 13
        NOS
    		 26 26
        Other
    		 9 9
    Mini Mental Score (MMS)
    Units: MMS score
        median (full range (min-max))
    		 28.0 (19.0 to 30.0) -

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel - Carboplatin
    Reporting group description
    		 -
    Reporting group title
    Arm A - Follow-up
    Reporting group description
    		 -

    Reporting group title
    Arm B1 - Maintenance Pemetrexed
    Reporting group description
    		 Pemetrexed for patients with non-squamous cell carcinoma

    Reporting group title
    ARM B2 - Maintenance Gemcitabine
    Reporting group description
    		 Gemcitabine for patients with squamous cell carcinoma

    Reporting group title
    ARM B - Maintenance
    Reporting group description
    		 Pemetrexed for patients with non-squamous cell carcinoma Gemcitabine for patients with squamous cell carcinoma
    Reporting group title
    Erlotinib
    Reporting group description
    		 Second line fixed with erlotinib in case of disease progression (RECIST 1.1).

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Time from randomisation to death from any cause.
    End point type
    Primary
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up ARM B - Maintenance
    Number of subjects analysed
    166
    162
    Units: months
        median (confidence interval 95%)
    14.1 (12.0 to 17.0)
    14.0 (10.9 to 16.9)
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    Time from randomisation to death from any cause.
    Comparison groups
    Arm A - Follow-up v ARM B - Maintenance
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.2
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Number of maintenance cycles received

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    End point title
    		 Number of maintenance cycles received
    End point description
    End point type
    Secondary
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm B1 - Maintenance Pemetrexed ARM B2 - Maintenance Gemcitabine
    Number of subjects analysed
    109
    43
    Units: number of cycles
        median (full range (min-max))
    4 (1 to 38)
    4 (1 to 31)
    No statistical analyses for this end point

    Secondary: Progression Free survival

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    End point title
    		 Progression Free survival
    End point description
    End point type
    Secondary
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up ARM B - Maintenance
    Number of subjects analysed
    166
    162
    Units: months
        median (full range (min-max))
    2.7 (2.6 to 3.1)
    5.7 (4.8 to 7.1)
    No statistical analyses for this end point

    Secondary: Duration of response from randomization

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    End point title
    		 Duration of response from randomization
    End point description
    Duration of the response or stabilization obtained from the maintenance therapy.
    End point type
    Secondary
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up Arm B1 - Maintenance Pemetrexed ARM B2 - Maintenance Gemcitabine ARM B - Maintenance
    Number of subjects analysed
    166
    119
    43
    162
    Units: months
        median (full range (min-max))
    2.7 (0 to 41.8)
    5.6 (0 to 45.8)
    6.8 (0 to 36.9)
    5.7 (0 to 45.8)
    No statistical analyses for this end point

    Secondary: Patients receiving second line erlotinib

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    End point title
    		 Patients receiving second line erlotinib
    End point description
    End point type
    Secondary
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up ARM B - Maintenance
    Number of subjects analysed
    166
    162
    Units: Number of subjects
    109
    68
    No statistical analyses for this end point

    Secondary: Evalutation of clinical prognostic survival factors

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    End point title
    		 Evalutation of clinical prognostic survival factors
    End point description
    Univariate analysis of all stratification criteria for randomization. 0 to 1 : in favor of maintenance arm 1 to 2 : in favor of follow-up arm
    End point type
    Secondary
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Paclitaxel - Carboplatin
    Number of subjects analysed
    627
    Units: Hazard Ratio
    number (confidence interval 95%)
        ALL
    0.91 (0.71 to 1.17)
        ECOG Performans Status 0-1
    1.03 (0.78 to 1.36)
        ECOG Performans Status 2
    0.70 (0.40 to 1.23)
        Non-squamous cell carcinoma
    0.82 (0.61 to 1.09)
        Squamous cell carcinoma
    1.26 (0.78 to 2.05)
        Stable response after 4 cycles
    0.94 (0.67 to 1.33)
        Objective response after 4 cycles
    0.97 (0.68 to 1.39)
        Age : 80 years old and over
    1.01 (0.58 to 1.74)
        Age : < 80 years old
    0.90 (0.68 to 1.18)
    No statistical analyses for this end point

    Post-hoc: Response rate according to RECIST 1.1 - Second line

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    End point title
    		 Response rate according to RECIST 1.1 - Second line
    End point description
    End point type
    Post-hoc
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up ARM B - Maintenance
    Number of subjects analysed
    133 [1]
    103 [2]
    Units: Number of subjects
        Complete response
    1
    1
        Partial response
    8
    7
        Stable
    40
    30
        Progression
    61
    42
        Not done/Not evaluable
    5
    5
        Missing
    18
    18
    Notes
    [1] - Patients with second-line systemic post-treatment
    [2] - Patients with second-line systemic post-treatment
    No statistical analyses for this end point

    Post-hoc: Overall Survival from second line

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    End point title
    		 Overall Survival from second line
    End point description
    End point type
    Post-hoc
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up ARM B - Maintenance
    Number of subjects analysed
    133 [3]
    103 [4]
    Units: months
        median (confidence interval 95%)
    11.7 (8.8 to 14.9)
    9.2 (5.9 to 13.2)
    Notes
    [3] - Patients with second-line systemic post-treatment
    [4] - Patients with second-line systemic post-treatment
    No statistical analyses for this end point

    Post-hoc: Progression Free survival from second line

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    End point title
    		 Progression Free survival from second line
    End point description
    End point type
    Post-hoc
    End point timeframe
    39.7 months (median follow-up)
    End point values
    		 Arm A - Follow-up ARM B - Maintenance
    Number of subjects analysed
    133 [5]
    103 [6]
    Units: Months
        median (confidence interval 95%)
    2.9 (2.1 to 4)
    3.2 (2.2 to 4.8)
    Notes
    [5] - Patients with second-line systemic post-treatment
    [6] - Patients with second-line systemic post-treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events have to be reported from inclusion to 30 day following the end of administration of study treatments.
    Adverse event reporting additional description
    The maximal grade of adverse events was collected by cycle of treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Induction
    Reporting group description
    		 -

    Reporting group title
    Arm A - Follow-up
    Reporting group description
    		 -

    Reporting group title
    Arm B1 - Maintenance Pemetrexed
    Reporting group description
    		 The safety population - Arm B Pemetrexed will be defined as all patients who received at least one dose of pemetrexed.

    Reporting group title
    Arm B2 - Maintenance Gemcitabine
    Reporting group description
    		 The safety population - Arm B Gemcitabine will be defined as all patients who received at least one dose of Gemcitabine.

    Serious adverse events
    		 Induction Arm A - Follow-up Arm B1 - Maintenance Pemetrexed Arm B2 - Maintenance Gemcitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    220 / 623 (35.31%)
    2 / 166 (1.20%)
    38 / 109 (34.86%)
    24 / 43 (55.81%)
         number of deaths (all causes)
    53
    134
    93
    31
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial carcinoma
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    11 / 623 (1.77%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 623 (1.44%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 623 (0.80%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    34 / 623 (5.46%)
    1 / 166 (0.60%)
    8 / 109 (7.34%)
    3 / 43 (6.98%)
         occurrences causally related to treatment / all
    14 / 37
    0 / 1
    3 / 8
    1 / 3
         deaths causally related to treatment / all
    0 / 15
    0 / 0
    0 / 2
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 623 (0.80%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sense of oppression
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    4 / 623 (0.64%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    13 / 623 (2.09%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 623 (0.64%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Laryngeal dyspnoea
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    12 / 623 (1.93%)
    0 / 166 (0.00%)
    6 / 109 (5.50%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    5 / 12
    0 / 0
    1 / 6
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    0 / 0
    Pleural effusion
         subjects affected / exposed
    9 / 623 (1.44%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    7 / 623 (1.12%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    3 / 43 (6.98%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    7 / 623 (1.12%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis chemical
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 623 (0.80%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    7 / 623 (1.12%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
    1 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paralysis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 623 (2.09%)
    0 / 166 (0.00%)
    6 / 109 (5.50%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    11 / 13
    0 / 0
    6 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    6 / 623 (0.96%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    12 / 623 (1.93%)
    0 / 166 (0.00%)
    3 / 109 (2.75%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    13 / 13
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    3 / 3
    0 / 0
    2 / 2
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    5 / 623 (0.80%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 623 (1.12%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 623 (0.80%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hydrocholecystis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 623 (0.96%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    4 / 623 (0.64%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 623 (0.64%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    6 / 623 (0.96%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 623 (0.64%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    3 / 43 (6.98%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 623 (0.32%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    22 / 623 (3.53%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    14 / 22
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    5 / 11
    0 / 0
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    6 / 623 (0.96%)
    1 / 166 (0.60%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    1 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    5 / 623 (0.80%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 623 (0.48%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 623 (0.00%)
    0 / 166 (0.00%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    0 / 109 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Induction Arm A - Follow-up Arm B1 - Maintenance Pemetrexed Arm B2 - Maintenance Gemcitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    602 / 623 (96.63%)
    135 / 166 (81.33%)
    106 / 109 (97.25%)
    42 / 43 (97.67%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    318 / 623 (51.04%)
    42 / 166 (25.30%)
    57 / 109 (52.29%)
    16 / 43 (37.21%)
         occurrences all number
    320
    58
    118
    25
    Chest pain
         subjects affected / exposed
    36 / 623 (5.78%)
    12 / 166 (7.23%)
    7 / 109 (6.42%)
    2 / 43 (4.65%)
         occurrences all number
    38
    12
    8
    2
    Fatigue
         subjects affected / exposed
    34 / 623 (5.46%)
    4 / 166 (2.41%)
    8 / 109 (7.34%)
    4 / 43 (9.30%)
         occurrences all number
    34
    5
    12
    12
    General physical health deterioration
         subjects affected / exposed
    37 / 623 (5.94%)
    2 / 166 (1.20%)
    16 / 109 (14.68%)
    2 / 43 (4.65%)
         occurrences all number
    39
    2
    17
    2
    Oedema peripheral
         subjects affected / exposed
    51 / 623 (8.19%)
    5 / 166 (3.01%)
    30 / 109 (27.52%)
    8 / 43 (18.60%)
         occurrences all number
    52
    8
    65
    11
    Pyrexia
         subjects affected / exposed
    30 / 623 (4.82%)
    3 / 166 (1.81%)
    15 / 109 (13.76%)
    9 / 43 (20.93%)
         occurrences all number
    30
    5
    23
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    106 / 623 (17.01%)
    33 / 166 (19.88%)
    16 / 109 (14.68%)
    11 / 43 (25.58%)
         occurrences all number
    106
    43
    23
    18
    Dyspnoea
         subjects affected / exposed
    159 / 623 (25.52%)
    40 / 166 (24.10%)
    30 / 109 (27.52%)
    14 / 43 (32.56%)
         occurrences all number
    159
    52
    52
    20
    Lung disorder
         subjects affected / exposed
    12 / 623 (1.93%)
    0 / 166 (0.00%)
    6 / 109 (5.50%)
    3 / 43 (6.98%)
         occurrences all number
    12
    0
    6
    3
    Productive cough
         subjects affected / exposed
    24 / 623 (3.85%)
    3 / 166 (1.81%)
    8 / 109 (7.34%)
    2 / 43 (4.65%)
         occurrences all number
    24
    3
    8
    2
    Chest pain
         subjects affected / exposed
    5 / 623 (0.80%)
    4 / 166 (2.41%)
    1 / 109 (0.92%)
    0 / 43 (0.00%)
         occurrences all number
    5
    4
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 623 (2.41%)
    0 / 166 (0.00%)
    13 / 109 (11.93%)
    4 / 43 (9.30%)
         occurrences all number
    15
    0
    21
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 623 (3.53%)
    0 / 166 (0.00%)
    19 / 109 (17.43%)
    4 / 43 (9.30%)
         occurrences all number
    22
    0
    27
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    21 / 623 (3.37%)
    0 / 166 (0.00%)
    8 / 109 (7.34%)
    1 / 43 (2.33%)
         occurrences all number
    21
    0
    11
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    32 / 623 (5.14%)
    3 / 166 (1.81%)
    11 / 109 (10.09%)
    1 / 43 (2.33%)
         occurrences all number
    33
    5
    12
    3
    Weight decreased
         subjects affected / exposed
    78 / 623 (12.52%)
    6 / 166 (3.61%)
    11 / 109 (10.09%)
    2 / 43 (4.65%)
         occurrences all number
    78
    6
    16
    4
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    8 / 623 (1.28%)
    0 / 166 (0.00%)
    2 / 109 (1.83%)
    4 / 43 (9.30%)
         occurrences all number
    8
    0
    2
    4
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    60 / 623 (9.63%)
    18 / 166 (10.84%)
    9 / 109 (8.26%)
    5 / 43 (11.63%)
         occurrences all number
    60
    29
    18
    15
    Paraesthesia
         subjects affected / exposed
    97 / 623 (15.57%)
    14 / 166 (8.43%)
    17 / 109 (15.60%)
    6 / 43 (13.95%)
         occurrences all number
    103
    23
    23
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    449 / 623 (72.07%)
    62 / 166 (37.35%)
    81 / 109 (74.31%)
    34 / 43 (79.07%)
         occurrences all number
    450
    79
    186
    77
    Febrile neutropenia
         subjects affected / exposed
    17 / 623 (2.73%)
    0 / 166 (0.00%)
    8 / 109 (7.34%)
    2 / 43 (4.65%)
         occurrences all number
    17
    0
    8
    2
    Leukopenia
         subjects affected / exposed
    79 / 623 (12.68%)
    0 / 166 (0.00%)
    11 / 109 (10.09%)
    6 / 43 (13.95%)
         occurrences all number
    79
    0
    16
    7
    Lymphopenia
         subjects affected / exposed
    68 / 623 (10.91%)
    5 / 166 (3.01%)
    11 / 109 (10.09%)
    8 / 43 (18.60%)
         occurrences all number
    68
    8
    16
    12
    Neutropenia
         subjects affected / exposed
    363 / 623 (58.27%)
    6 / 166 (3.61%)
    50 / 109 (45.87%)
    19 / 43 (44.19%)
         occurrences all number
    370
    6
    88
    25
    Thrombocytopenia
         subjects affected / exposed
    277 / 623 (44.46%)
    6 / 166 (3.61%)
    41 / 109 (37.61%)
    23 / 43 (53.49%)
         occurrences all number
    279
    7
    65
    38
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    13 / 109 (11.93%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0
    21
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    100 / 623 (16.05%)
    4 / 166 (2.41%)
    16 / 109 (14.68%)
    3 / 43 (6.98%)
         occurrences all number
    100
    6
    24
    3
    Diarrhoea
         subjects affected / exposed
    117 / 623 (18.78%)
    3 / 166 (1.81%)
    15 / 109 (13.76%)
    2 / 43 (4.65%)
         occurrences all number
    118
    3
    21
    2
    Nausea
         subjects affected / exposed
    172 / 623 (27.61%)
    2 / 166 (1.20%)
    28 / 109 (25.69%)
    1 / 43 (2.33%)
         occurrences all number
    175
    2
    42
    3
    Vomiting
         subjects affected / exposed
    76 / 623 (12.20%)
    1 / 166 (0.60%)
    11 / 109 (10.09%)
    1 / 43 (2.33%)
         occurrences all number
    60
    1
    15
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    90 / 623 (14.45%)
    6 / 166 (3.61%)
    3 / 109 (2.75%)
    2 / 43 (4.65%)
         occurrences all number
    90
    9
    7
    2
    Pruritus
         subjects affected / exposed
    11 / 623 (1.77%)
    2 / 166 (1.20%)
    7 / 109 (6.42%)
    1 / 43 (2.33%)
         occurrences all number
    11
    3
    8
    1
    Rash
         subjects affected / exposed
    9 / 623 (1.44%)
    3 / 166 (1.81%)
    9 / 109 (8.26%)
    1 / 43 (2.33%)
         occurrences all number
    9
    3
    12
    3
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    66 / 623 (10.59%)
    15 / 166 (9.04%)
    25 / 109 (22.94%)
    5 / 43 (11.63%)
         occurrences all number
    66
    22
    56
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 623 (5.78%)
    10 / 166 (6.02%)
    5 / 109 (4.59%)
    2 / 43 (4.65%)
         occurrences all number
    41
    11
    7
    5
    Back pain
         subjects affected / exposed
    33 / 623 (5.30%)
    12 / 166 (7.23%)
    14 / 109 (12.84%)
    3 / 43 (6.98%)
         occurrences all number
    33
    17
    17
    3
    Musculoskeletal pain
         subjects affected / exposed
    10 / 623 (1.61%)
    0 / 166 (0.00%)
    4 / 109 (3.67%)
    3 / 43 (6.98%)
         occurrences all number
    10
    0
    6
    3
    Pain in extremity
         subjects affected / exposed
    21 / 623 (3.37%)
    7 / 166 (4.22%)
    5 / 109 (4.59%)
    4 / 43 (9.30%)
         occurrences all number
    21
    7
    6
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    20 / 623 (3.21%)
    7 / 166 (4.22%)
    11 / 109 (10.09%)
    1 / 43 (2.33%)
         occurrences all number
    21
    7
    14
    1
    Conjunctivitis
         subjects affected / exposed
    3 / 623 (0.48%)
    1 / 166 (0.60%)
    9 / 109 (8.26%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    15
    1
    Erysipelas
         subjects affected / exposed
    1 / 623 (0.16%)
    0 / 166 (0.00%)
    10 / 109 (9.17%)
    2 / 43 (4.65%)
         occurrences all number
    1
    0
    17
    2
    Lung infection
         subjects affected / exposed
    9 / 623 (1.44%)
    5 / 166 (3.01%)
    7 / 109 (6.42%)
    3 / 43 (6.98%)
         occurrences all number
    9
    7
    7
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    133 / 623 (21.35%)
    8 / 166 (4.82%)
    26 / 109 (23.85%)
    4 / 43 (9.30%)
         occurrences all number
    135
    10
    41
    8
    Hypoalbuminaemia
         subjects affected / exposed
    41 / 623 (6.58%)
    6 / 166 (3.61%)
    10 / 109 (9.17%)
    3 / 43 (6.98%)
         occurrences all number
    41
    6
    16
    5
    Hypocalcaemia
         subjects affected / exposed
    42 / 623 (6.74%)
    3 / 166 (1.81%)
    7 / 109 (6.42%)
    1 / 43 (2.33%)
         occurrences all number
    42
    4
    9
    1
    Hypokalaemia
         subjects affected / exposed
    16 / 623 (2.57%)
    2 / 166 (1.20%)
    6 / 109 (5.50%)
    1 / 43 (2.33%)
         occurrences all number
    16
    2
    7
    1
    Hyponatraemia
         subjects affected / exposed
    35 / 623 (5.62%)
    1 / 166 (0.60%)
    4 / 109 (3.67%)
    0 / 43 (0.00%)
         occurrences all number
    35
    1
    9
    0
    Hyperglycaemia
         subjects affected / exposed
    31 / 623 (4.98%)
    4 / 166 (2.41%)
    3 / 109 (2.75%)
    3 / 43 (6.98%)
         occurrences all number
    31
    5
    3
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2013
    - Clarification of inclusion/exclusion criteria * Patients with active or symptomatic central nervous system metastases are ineligible. Patients with a history of symptomatic central nervous system metastases or spinal cord compression may be included if they have been treated (surgery or radiotherapy) and have become asymptomatic. Oral corticosteroids are allowed provided that the dose has been stable for at least 4 weeks prior to the start of treatment. * The criterion for radiation therapy is moved to maintenance eligibility criteria and updated for: "No concurrent radiation therapy, except for palliative localized non-spinal bone radiation therapy, with a 2 week delay between the administration of gemcitabine and the start of radiation therapy or the end of radiation therapy before the start of treatment, which may be shortened to 8 days if required by the patient's clinical condition. In the case of spinal irradiation, irradiation should be avoided as much as possible within 4 weeks after the administration of gemcitabine." - Clarification of the time frame to start treatment: the maximum time between inclusion and the start of induction treatment is 2 weeks. The maximum time between Day 1 of the 4th cycle of induction therapy and Day 1 of maintenance is 42 days. The second line should start no later than 3 weeks after the assessment showing progression. - Correction of the summary table of examinations: * Deletion of the geriatric depression scale at each evaluation (to be done only at inclusion and after 4 cycles of induction). * Biology at Day 8 and Day 15 are only to be done for patients receiving chemotherapy. - Chemotherapy doses will be capped at 400 mg/m² for carboplatin and at 2m² of body surface area in general. - Calvert's formula will be used for calculation of carboplatin dose.
    18 Aug 2014
    - Correction of the criterion on peripheral neuropathy (possible inclusion of patients with grade 1 neuropathy). - Patients with a history of prostate cancer less than 5 years old may be included under certain conditions. - Clarification of the tumor assessment at randomization: thoracic CT with adrenal sections, abdominal ultrasound and/or abdominal CT and brain CT or MRI are to be performed at randomization (those exams will be the reference for assessment during maintenance and observation).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Choice of the geriatric indexes was somewhat arbitrary ; Relatively high number of missing values pertaining to the geriatric indexes at the time of randomisation ; Erlotinib is no longer recommended as salvage therapy in pts without EGFR mutations

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32898792
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