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    Clinical Trial Results:
    A Phase II, Double-Blind, Placebo-Controlled, Randomized Study Evaluating the Safety and Efficacy of Carboplatin/Paclitaxel and Carboplatin/Paclitaxel/Bevacizumab with and without GDC-0941 in Patients with Previously Untreated Advanced or Recurrent Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    2011-002893-21
    Trial protocol
    DE   HU   ES   NL   GB   IT  
    Global end of trial date
    30 Mar 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Apr 2017
    First version publication date
    13 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GO27912
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01493843
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    06 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy (as measured by Progression Free Survival) of pictilisib in combination with carboplatin (C) + paclitaxel (P) in subjects with squamous non-small cell lung cancer (NSCLC) and in combination with carboplatin (C) + paclitaxel (P) + bevacizumab (B) in subjects with non-squamous NSCLC.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Jan 2012
    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
    Spain: 31
    Country: Number of subjects enrolled
    Ukraine: 36
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 155
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Brazil: 16
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Hungary: 32
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Russian Federation: 90
    Worldwide total number of subjects
    501
    EEA total number of subjects
    165
    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)
    299
    From 65 to 84 years
    199
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    For Arms A and B subjects must have histologically documented advanced (Stage IV) or recurrent squamous NSCLC and for Arms C, D, E and F advanced (Stage IV) or recurrent non-squamous NSCLC.

    Pre-assignment
    Screening details
    Subjects with squamous NSCLC were checked for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) amplification status and subjects with non-squamous NSCLC for phosphatase and tensin homolog (PTEN) loss/low status.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A: 340 mg pictilisib + CP
    Arm description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P).
    Arm type
    Experimental

    Investigational medicinal product name
    pictilisib
    Investigational medicinal product code
    Other name
    GDC-0941
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pictilisib, 340 mg, was taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, pictilisib was taken once daily continuously.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered 200 milligrams per square metre (mg/m^2) IV on Day 1 of each 21-day cycle for a maximum of four cycles.

    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 was administered intravenously (IV) to achieve an initial target area under the concentration curve (AUC) of 6 milligrams per millilitre per minute (mg/mL per min) on Day 1 of each 21-day cycle for a maximum of four cycles.

    Arm title
    Arm B: Placebo + CP
    Arm description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm A during the first 4 cycles with carboplatin + paclitaxel or after chemotherapy had been completed (Cycle >/= 5).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo corresponding to 340 mg pictilisib was taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, placebo was taken once daily continuously.

    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 was administered IV to achieve an initial target AUC of 6 mg/mL per min on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered 200 mg/m^2 IV on Day 1 of each 21-day cycle for a maximum of four cycles.

    Arm title
    Arm C: 340 mg pictilisib + CPB
    Arm description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B).
    Arm type
    Experimental

    Investigational medicinal product name
    pictilisib
    Investigational medicinal product code
    Other name
    GDC-0941
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pictilisib, 340 mg, was taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, pictilisib was taken once daily continuously.

    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 was administered IV to achieve an initial target AUC of 6 mg/mL per min on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered 200 mg/m^2 IV on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab, 15 milligrams per kilogram (mg/kg) was administered IV at Day 1 of each 21-day cycle for a maximum of 34 cycles.

    Arm title
    Arm D: Placebo + CPB
    Arm description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm C during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo corresponding to 340 mg pictilisib was taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, placebo was taken once daily continuously.

    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 was administered IV to achieve an initial target AUC of 6 mg/mL per min on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered 200 mg/m^2 IV on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab, 15 milligrams per kilogram (mg/kg) was administered IV at Day 1 of each 21-day cycle for a maximum of 34 cycles.

    Arm title
    Arm E: 260 mg pictilisib + CPB
    Arm description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B).
    Arm type
    Experimental

    Investigational medicinal product name
    pictilisib
    Investigational medicinal product code
    Other name
    GDC-0941
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pictilisib, 260 mg, was taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, pictilisib was taken once daily continuously.

    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 was administered IV to achieve an initial target AUC of 6 mg/mL per min on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered 200 mg/m^2 IV on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab, 15 milligrams per kilogram (mg/kg) was administered IV at Day 1 of each 21-day cycle for a maximum of 34 cycles.

    Arm title
    Arm F: Placebo + CPB
    Arm description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm E during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo corresponding to 260 mg pictilisib was taken orally once daily on Days 1-14 of a 21-day cycle for four cycles. Starting with Cycle 5, placebo was taken once daily continuously.

    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 was administered IV to achieve an initial target AUC of 6 mg/mL per min on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered 200 mg/m^2 IV on Day 1 of each 21-day cycle for a maximum of four cycles.

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab, 15 milligrams per kilogram (mg/kg) was administered IV at Day 1 of each 21-day cycle for a maximum of 34 cycles.

    Number of subjects in period 1
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Started
    126
    125
    79
    79
    62
    30
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    126
    125
    79
    79
    62
    30
         Study Terminated by Sponsor
    24
    30
    8
    11
    11
    6
         Death
    75
    78
    59
    57
    43
    21
         Withdrawal by Subject
    7
    6
    5
    3
    3
    1
         Other
    15
    7
    5
    4
    5
    2
         Unknown
    1
    -
    1
    -
    -
    -
         Lost to follow-up
    4
    4
    1
    4
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    -

    Reporting group values
    Overall Period Total
    Number of subjects
    501 501
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    299 299
        From 65-84 years
    199 199
        85 years and over
    3 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    62 ± 9.7 -
    Gender Categorical
    Units: Subjects
        Female
    140 140
        Male
    361 361

    End points

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    End points reporting groups
    Reporting group title
    Arm A: 340 mg pictilisib + CP
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P).

    Reporting group title
    Arm B: Placebo + CP
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm A during the first 4 cycles with carboplatin + paclitaxel or after chemotherapy had been completed (Cycle >/= 5).

    Reporting group title
    Arm C: 340 mg pictilisib + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B).

    Reporting group title
    Arm D: Placebo + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm C during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5).

    Reporting group title
    Arm E: 260 mg pictilisib + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B).

    Reporting group title
    Arm F: Placebo + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm E during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5).

    Subject analysis set title
    Arm A Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.

    Subject analysis set title
    Arm B Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm A during the first 4 cycles with carboplatin + paclitaxel or after chemotherapy had been completed (Cycle >/= 5). Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.

    Subject analysis set title
    Arm C Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B). Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.

    Subject analysis set title
    Arm D Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm C during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5). Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.

    Subject analysis set title
    Arm E Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B). Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.

    Subject analysis set title
    Arm F Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm E during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5). Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from randomisation to NSCLC disease progression as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause on study (</= 30 days after the last dose of study treatment), whichever occurs first. Progression according to RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimetre (mm) or the appearance of one or more new lesions. Tumor assessments were performed by computed tomography (CT) scan and/or magnetic resonance imaging (MRI). Intent-to-Treat (ITT) population included all randomised subjects with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Primary
    End point timeframe
    Up to approximately 2.5 years
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Number of subjects analysed
    94
    90
    79
    79
    62
    30
    Units: months
        median (confidence interval 90%)
    5.45 (4.24 to 6.74)
    5.49 (4.34 to 5.65)
    6.87 (5.52 to 9.66)
    6.08 (5.55 to 6.9)
    6.93 (4.63 to 8.28)
    6.6 (5.49 to 8.31)
    Statistical analysis title
    Arm A versus Arm B
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Arm A: 340 mg pictilisib + CP v Arm B: Placebo + CP
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5327
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.21
    Statistical analysis title
    Arm C versus Arm D
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Arm C: 340 mg pictilisib + CPB v Arm D: Placebo + CPB
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3496
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.15
    Statistical analysis title
    Arm E versus Arm F
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Arm E: 260 mg pictilisib + CPB v Arm F: Placebo + CPB
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8866
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.64

    Primary: PFS in Subjects with PIK3CA Amplification

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    End point title
    PFS in Subjects with PIK3CA Amplification [1]
    End point description
    PFS was defined as the time from randomisation to NSCLC disease progression as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause on study (</= 30 days after the last dose of study treatment), whichever occurs first. Progression according to RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Tumor assessments were performed by CT scan and/or MRI. PIK3CA amplified subjects in the ITT population included all randomised subjects with PIK3CA amplification with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Primary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PIK3CA amplification were only represented in arms A and B. Therefore, only arms A and B were included in this endpoint.
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP
    Number of subjects analysed
    30
    27
    Units: months
        median (confidence interval 90%)
    6.6 (4.5 to 6.93)
    5.29 (4.27 to 5.55)
    Statistical analysis title
    PIK3CA amplified subjects Arm A versus Arm B
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Arm A: 340 mg pictilisib + CP v Arm B: Placebo + CP
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5388
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    1.44

    Primary: PFS in Subjects with PTEN Loss/low

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    End point title
    PFS in Subjects with PTEN Loss/low [2]
    End point description
    PFS was defined as the time from randomisation to NSCLC disease progression as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death from any cause on study (</= 30 days after the last dose of study treatment), whichever occurs first. Progression according to RECIST v1.1 is defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Tumor assessments were performed by CT scan and/or MRI. Subjects with PTEN loss/low in the ITT population included all randomised subjects with PTEN loss/low with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Primary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PTEN loss/low were only represented in arms C and D. Therefore, only arms C and D were included in this endpoint.
    End point values
    Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB
    Number of subjects analysed
    28
    46
    Units: months
        median (confidence interval 90%)
    6.9 (5.52 to 9.69)
    5.62 (5.13 to 6.08)
    Statistical analysis title
    PTEN loss/low in Arm C versus Arm D
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Arm C: 340 mg pictilisib + CPB v Arm D: Placebo + CPB
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2199
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    1.13

    Secondary: Objective Tumor Response

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    End point title
    Objective Tumor Response
    End point description
    Objective tumor response was assessed by the investigator using RECIST v1.1 and had to be confirmed >/= 28 days after initial response. Objective tumor response was defined as percentage of subjects with partial response (PR) or complete response (CR). PR: >=30% decrease in the sum of the longest diameter of target lesions; CR: disappearance of all target lesions; Objective tumor response = CR + PR. Tumor assessments were performed by CT scan and/or MRI. ITT population included all randomised subjects with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Number of subjects analysed
    94
    90
    79
    79
    62
    30
    Units: Percentage of subjects
        number (not applicable)
    24.5
    30
    36.7
    29.1
    25.8
    43.3
    No statistical analyses for this end point

    Secondary: Objective Tumor Response in Subjects with PIK3CA Amplification

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    End point title
    Objective Tumor Response in Subjects with PIK3CA Amplification [3]
    End point description
    Objective tumor response was assessed by the investigator using RECIST v1.1 and had to be confirmed >/= 28 days after initial response. Objective tumor response was defined as percentage of subjects with partial response (PR) or complete response (CR). PR: >=30% decrease in the sum of the longest diameter of target lesions; CR: disappearance of all target lesions; Objective tumor response = CR + PR. Tumor assessments were performed by CT scan and/or MRI. ITT population included all randomised subjects with PIK3CA amplification with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PIK3CA amplification were only represented in arms A and B. Therefore, only arms A and B were included in this endpoint.
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP
    Number of subjects analysed
    30
    27
    Units: Percentage of subjects
        number (not applicable)
    16.7
    33.3
    No statistical analyses for this end point

    Secondary: Objective Tumor Response in Subjects with PTEN Loss/low

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    End point title
    Objective Tumor Response in Subjects with PTEN Loss/low [4]
    End point description
    Objective tumor response was assessed by the investigator using RECIST v1.1 and had to be confirmed >/= 28 days after initial response. Objective tumor response was defined as percentage of subjects with partial response (PR) or complete response (CR). PR: >=30% decrease in the sum of the longest diameter of target lesions; CR: disappearance of all target lesions; Objective tumor response = CR + PR. Tumor assessments were performed by CT scan and/or MRI. ITT population included all randomised subjects with PTEN loss/low with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PTEN loss/low were only represented in arms C and D. Therefore, only arms C and D were included in this endpoint.
    End point values
    Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB
    Number of subjects analysed
    28
    46
    Units: Percentage of subjects
        number (not applicable)
    39.3
    28.3
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (DoR)

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    End point title
    Duration of Objective Response (DoR)
    End point description
    DoR was defined as the time from first observation of an objective tumor response until first observation of disease progression as assessed by the investigator using RECIST v1.1. Objective tumor response was defined as percentage of participants with partial response (PR) or complete response (CR). PR: >=30% decrease in the sum of the longest diameter of target lesions; CR: disappearance of all target lesions; Objective tumor response = CR + PR. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Tumor assessments were performed by CT scan and/or MRI. ITT population included all randomised subjects with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [5] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [6] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [7] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [8] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [9] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [10] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    No statistical analyses for this end point

    Secondary: DoR in Subjects with PIK3CA Amplification

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    End point title
    DoR in Subjects with PIK3CA Amplification [11]
    End point description
    DoR was defined as the time from first observation of an objective tumor response until first observation of disease progression as assessed by the investigator using RECIST v1.1. Objective tumor response was defined as percentage of participants with partial response (PR) or complete response (CR). PR: >=30% decrease in the sum of the longest diameter of target lesions; CR: disappearance of all target lesions; Objective tumor response = CR + PR. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Tumor assessments were performed by CT scan and/or MRI. ITT population included all randomised subjects with PIK3CA amplification with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PIK3CA amplification were only represented in arms A and B. Therefore, only arms A and B were included in this endpoint.
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [12] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [13] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    No statistical analyses for this end point

    Secondary: DoR in Subjects with PTEN Loss/low

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    End point title
    DoR in Subjects with PTEN Loss/low [14]
    End point description
    DoR was defined as the time from first observation of an objective tumor response until first observation of disease progression as assessed by the investigator using RECIST v1.1. Objective tumor response was defined as percentage of participants with partial response (PR) or complete response (CR). PR: >=30% decrease in the sum of the longest diameter of target lesions; CR: disappearance of all target lesions; Objective tumor response = CR + PR. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Tumor assessments were performed by CT scan and/or MRI. ITT population included all randomised subjects with PTEN loss/low with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PTEN loss/low were only represented in arms C and D. Therefore, only arms C and D were included in this endpoint.
    End point values
    Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [15] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    [16] - The Sponsor has discontinued the clinical development of pictilisib. DoR data were not analysed.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from randomisation until death from any cause. ITT population included all randomised subjects with subjects allocated to the treatment arm to which they were randomised. 9999=NE=not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Number of subjects analysed
    94
    90
    79
    79
    62
    30
    Units: months
        median (confidence interval 90%)
    12.16 (9.23 to 14.92)
    12.39 (9.26 to 15.05)
    13.57 (12.12 to 20.7)
    16.07 (10.51 to 18.63)
    11.47 (8.02 to 15.8)
    14.23 (9 to 9999)
    No statistical analyses for this end point

    Secondary: OS in Subjects with PIK3CA Amplification

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    End point title
    OS in Subjects with PIK3CA Amplification [17]
    End point description
    OS was defined as the time from randomisation until death from any cause. ITT population included all randomised subjects with PIK3CA amplification with subjects allocated to the treatment arm to which they were randomised. 9999=NE=not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PIK3CA amplification were only represented in arms A and B. Therefore, only arms A and B were included in this endpoint.
    End point values
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP
    Number of subjects analysed
    30
    27
    Units: months
        median (confidence interval 90%)
    15.05 (9.46 to 20.37)
    11.7 (8.51 to 9999)
    No statistical analyses for this end point

    Secondary: OS in Subjects with PTEN Loss/low

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    End point title
    OS in Subjects with PTEN Loss/low [18]
    End point description
    OS was defined as the time from randomisation until death from any cause. ITT population included all randomised subjects with PTEN loss/low with subjects allocated to the treatment arm to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2.5 years
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects with PTEN loss/low were only represented in arms C and D. Therefore, only arms C and D were included in this endpoint.
    End point values
    Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB
    Number of subjects analysed
    28
    46
    Units: months
        median (confidence interval 90%)
    14.52 (12.12 to 20.86)
    11.27 (8.28 to 18.14)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events

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    End point title
    Percentage of Subjects with Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    Arm A Safety Population Arm B Safety Population Arm C Safety Population Arm D Safety Population Arm E Safety Population Arm F Safety Population
    Number of subjects analysed
    133
    115
    82
    73
    59
    26
    Units: percentage of subjects
        number (not applicable)
    94.7
    97.4
    98.8
    100
    94.9
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 4 years
    Adverse event reporting additional description
    Safety population included all subjects, who received at least one dose of study treatment, with subjects allocated to the treatment arm associated with the regimen actually received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Arm A: 340 mg pictilisib + CP
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P).

    Reporting group title
    Arm B: Placebo + CP
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm A during the first 4 cycles with carboplatin + paclitaxel or after chemotherapy had been completed (Cycle >/= 5).

    Reporting group title
    Arm C: 340 mg pictilisib + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B).

    Reporting group title
    Arm D: Placebo + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 340 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm C during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5).

    Reporting group title
    Arm E: 260 mg pictilisib + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P) plus bevacizumab (B).

    Reporting group title
    Arm F: Placebo + CPB
    Reporting group description
    Subjects with advanced (Stage IV) or recurrent non-squamous NSCLC were administered placebo corresponding to 260 mg pictilisib plus carboplatin (C) plus paclitaxel (P). Subjects with investigator-assessed radiographic progression of NSCLC per RECIST 1.1 were allowed to cross over to Arm E during the first 4 cycles with carboplatin + paclitaxel + bevacizumab or after chemotherapy had been completed (Cycle >/= 5).

    Serious adverse events
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 133 (36.09%)
    34 / 115 (29.57%)
    40 / 82 (48.78%)
    33 / 73 (45.21%)
    32 / 59 (54.24%)
    12 / 26 (46.15%)
         number of deaths (all causes)
    17
    6
    5
    7
    13
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 115 (1.74%)
    0 / 82 (0.00%)
    2 / 73 (2.74%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer
         subjects affected / exposed
    5 / 133 (3.76%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    3 / 73 (4.11%)
    2 / 59 (3.39%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 3
    0 / 2
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    3 / 82 (3.66%)
    4 / 73 (5.48%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 5
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    2 / 73 (2.74%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    2 / 73 (2.74%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Eastern cooperative oncology group performance status worsened
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    3 / 133 (2.26%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 133 (3.01%)
    1 / 115 (0.87%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    4 / 59 (6.78%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    1 / 2
    1 / 1
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    4 / 133 (3.01%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    1 / 59 (1.69%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    2 / 73 (2.74%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    2 / 73 (2.74%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 133 (1.50%)
    4 / 115 (3.48%)
    3 / 82 (3.66%)
    3 / 73 (4.11%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    2 / 3
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 115 (1.74%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    2 / 2
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 115 (0.87%)
    1 / 82 (1.22%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    1 / 73 (1.37%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral amyloid angiopathy
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased vibratory sense
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of proprioception
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 2
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 115 (0.87%)
    3 / 82 (3.66%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    5 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    3 / 82 (3.66%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Oesophageal mass
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute prerenal failure
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    3 / 133 (2.26%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    1 / 82 (1.22%)
    3 / 73 (4.11%)
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    3 / 5
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 133 (6.02%)
    7 / 115 (6.09%)
    6 / 82 (7.32%)
    1 / 73 (1.37%)
    5 / 59 (8.47%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 9
    2 / 7
    2 / 6
    0 / 1
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    1 / 82 (1.22%)
    3 / 73 (4.11%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 133 (2.26%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    2 / 73 (2.74%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropod-borne disease
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal infection
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Toxic shock syndrome
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A: 340 mg pictilisib + CP Arm B: Placebo + CP Arm C: 340 mg pictilisib + CPB Arm D: Placebo + CPB Arm E: 260 mg pictilisib + CPB Arm F: Placebo + CPB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    122 / 133 (91.73%)
    109 / 115 (94.78%)
    81 / 82 (98.78%)
    71 / 73 (97.26%)
    55 / 59 (93.22%)
    25 / 26 (96.15%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 133 (6.02%)
    7 / 115 (6.09%)
    13 / 82 (15.85%)
    11 / 73 (15.07%)
    11 / 59 (18.64%)
    1 / 26 (3.85%)
         occurrences all number
    10
    10
    20
    14
    12
    1
    Hypotension
         subjects affected / exposed
    8 / 133 (6.02%)
    4 / 115 (3.48%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    2 / 59 (3.39%)
    1 / 26 (3.85%)
         occurrences all number
    8
    7
    1
    2
    6
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    33 / 133 (24.81%)
    32 / 115 (27.83%)
    30 / 82 (36.59%)
    21 / 73 (28.77%)
    21 / 59 (35.59%)
    9 / 26 (34.62%)
         occurrences all number
    53
    46
    58
    32
    34
    20
    Asthenia
         subjects affected / exposed
    22 / 133 (16.54%)
    24 / 115 (20.87%)
    26 / 82 (31.71%)
    20 / 73 (27.40%)
    18 / 59 (30.51%)
    5 / 26 (19.23%)
         occurrences all number
    47
    37
    42
    38
    33
    5
    Pyrexia
         subjects affected / exposed
    12 / 133 (9.02%)
    9 / 115 (7.83%)
    17 / 82 (20.73%)
    7 / 73 (9.59%)
    11 / 59 (18.64%)
    2 / 26 (7.69%)
         occurrences all number
    20
    10
    27
    7
    14
    2
    Chest pain
         subjects affected / exposed
    12 / 133 (9.02%)
    8 / 115 (6.96%)
    7 / 82 (8.54%)
    12 / 73 (16.44%)
    0 / 59 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    12
    10
    10
    13
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    9 / 133 (6.77%)
    1 / 115 (0.87%)
    9 / 82 (10.98%)
    3 / 73 (4.11%)
    5 / 59 (8.47%)
    2 / 26 (7.69%)
         occurrences all number
    11
    1
    17
    3
    5
    2
    Oedema peripheral
         subjects affected / exposed
    5 / 133 (3.76%)
    8 / 115 (6.96%)
    9 / 82 (10.98%)
    2 / 73 (2.74%)
    2 / 59 (3.39%)
    3 / 26 (11.54%)
         occurrences all number
    7
    12
    11
    3
    3
    3
    Pain
         subjects affected / exposed
    6 / 133 (4.51%)
    10 / 115 (8.70%)
    5 / 82 (6.10%)
    2 / 73 (2.74%)
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    6
    11
    6
    2
    2
    2
    Chills
         subjects affected / exposed
    3 / 133 (2.26%)
    1 / 115 (0.87%)
    6 / 82 (7.32%)
    5 / 73 (6.85%)
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences all number
    4
    1
    7
    6
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 133 (0.00%)
    6 / 115 (5.22%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    0
    6
    1
    2
    4
    2
    Influenza like illness
         subjects affected / exposed
    3 / 133 (2.26%)
    2 / 115 (1.74%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    4
    3
    1
    0
    3
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 115 (1.74%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    1
    0
    3
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 133 (6.77%)
    11 / 115 (9.57%)
    14 / 82 (17.07%)
    10 / 73 (13.70%)
    5 / 59 (8.47%)
    4 / 26 (15.38%)
         occurrences all number
    9
    13
    14
    13
    6
    5
    Depression
         subjects affected / exposed
    3 / 133 (2.26%)
    7 / 115 (6.09%)
    6 / 82 (7.32%)
    5 / 73 (6.85%)
    6 / 59 (10.17%)
    2 / 26 (7.69%)
         occurrences all number
    3
    7
    6
    6
    6
    2
    Anxiety
         subjects affected / exposed
    4 / 133 (3.01%)
    4 / 115 (3.48%)
    4 / 82 (4.88%)
    8 / 73 (10.96%)
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    4
    4
    4
    10
    6
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 115 (0.87%)
    3 / 82 (3.66%)
    5 / 73 (6.85%)
    2 / 59 (3.39%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    3
    6
    2
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    13 / 133 (9.77%)
    9 / 115 (7.83%)
    18 / 82 (21.95%)
    10 / 73 (13.70%)
    9 / 59 (15.25%)
    5 / 26 (19.23%)
         occurrences all number
    17
    10
    19
    12
    16
    5
    Platelet count decreased
         subjects affected / exposed
    11 / 133 (8.27%)
    4 / 115 (3.48%)
    6 / 82 (7.32%)
    3 / 73 (4.11%)
    3 / 59 (5.08%)
    2 / 26 (7.69%)
         occurrences all number
    17
    12
    7
    4
    6
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 133 (7.52%)
    9 / 115 (7.83%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    2 / 59 (3.39%)
    3 / 26 (11.54%)
         occurrences all number
    16
    11
    1
    2
    2
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 133 (5.26%)
    7 / 115 (6.09%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    2 / 59 (3.39%)
    4 / 26 (15.38%)
         occurrences all number
    9
    11
    1
    6
    2
    5
    Neutrophil count decreased
         subjects affected / exposed
    7 / 133 (5.26%)
    3 / 115 (2.61%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    4 / 59 (6.78%)
    1 / 26 (3.85%)
         occurrences all number
    14
    3
    2
    1
    5
    1
    White blood cell count decreased
         subjects affected / exposed
    2 / 133 (1.50%)
    5 / 115 (4.35%)
    2 / 82 (2.44%)
    0 / 73 (0.00%)
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    2
    7
    5
    0
    3
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 133 (2.26%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    2
    2
    3
    0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 133 (2.26%)
    0 / 115 (0.00%)
    3 / 82 (3.66%)
    0 / 73 (0.00%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    5
    0
    3
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 115 (1.74%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    1 / 59 (1.69%)
    2 / 26 (7.69%)
         occurrences all number
    3
    2
    1
    2
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 133 (16.54%)
    26 / 115 (22.61%)
    21 / 82 (25.61%)
    16 / 73 (21.92%)
    11 / 59 (18.64%)
    6 / 26 (23.08%)
         occurrences all number
    28
    33
    31
    21
    15
    7
    Dyspnoea
         subjects affected / exposed
    20 / 133 (15.04%)
    21 / 115 (18.26%)
    18 / 82 (21.95%)
    11 / 73 (15.07%)
    9 / 59 (15.25%)
    7 / 26 (26.92%)
         occurrences all number
    24
    24
    25
    17
    12
    11
    Epistaxis
         subjects affected / exposed
    4 / 133 (3.01%)
    5 / 115 (4.35%)
    23 / 82 (28.05%)
    18 / 73 (24.66%)
    16 / 59 (27.12%)
    7 / 26 (26.92%)
         occurrences all number
    4
    5
    34
    24
    18
    8
    Dysphonia
         subjects affected / exposed
    4 / 133 (3.01%)
    4 / 115 (3.48%)
    8 / 82 (9.76%)
    4 / 73 (5.48%)
    4 / 59 (6.78%)
    2 / 26 (7.69%)
         occurrences all number
    4
    4
    8
    6
    4
    2
    Haemoptysis
         subjects affected / exposed
    5 / 133 (3.76%)
    5 / 115 (4.35%)
    3 / 82 (3.66%)
    8 / 73 (10.96%)
    1 / 59 (1.69%)
    3 / 26 (11.54%)
         occurrences all number
    6
    6
    4
    10
    1
    3
    Productive cough
         subjects affected / exposed
    2 / 133 (1.50%)
    6 / 115 (5.22%)
    3 / 82 (3.66%)
    7 / 73 (9.59%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences all number
    4
    6
    3
    14
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    5 / 133 (3.76%)
    1 / 115 (0.87%)
    5 / 82 (6.10%)
    3 / 73 (4.11%)
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences all number
    9
    1
    5
    3
    3
    0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 115 (1.74%)
    3 / 82 (3.66%)
    1 / 73 (1.37%)
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    3
    1
    2
    2
    Pleural effusion
         subjects affected / exposed
    3 / 133 (2.26%)
    4 / 115 (3.48%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    4
    0
    0
    3
    0
    Hiccups
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    0 / 82 (0.00%)
    3 / 73 (4.11%)
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    0
    4
    3
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    1 / 82 (1.22%)
    2 / 73 (2.74%)
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    2
    3
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    2 / 82 (2.44%)
    4 / 73 (5.48%)
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    4
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    43 / 133 (32.33%)
    39 / 115 (33.91%)
    19 / 82 (23.17%)
    11 / 73 (15.07%)
    9 / 59 (15.25%)
    7 / 26 (26.92%)
         occurrences all number
    66
    66
    21
    23
    20
    15
    Neutropenia
         subjects affected / exposed
    31 / 133 (23.31%)
    35 / 115 (30.43%)
    23 / 82 (28.05%)
    15 / 73 (20.55%)
    13 / 59 (22.03%)
    8 / 26 (30.77%)
         occurrences all number
    50
    60
    40
    25
    21
    10
    Thrombocytopenia
         subjects affected / exposed
    23 / 133 (17.29%)
    12 / 115 (10.43%)
    14 / 82 (17.07%)
    7 / 73 (9.59%)
    5 / 59 (8.47%)
    3 / 26 (11.54%)
         occurrences all number
    40
    21
    29
    13
    5
    3
    Leukopenia
         subjects affected / exposed
    5 / 133 (3.76%)
    5 / 115 (4.35%)
    9 / 82 (10.98%)
    3 / 73 (4.11%)
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    5
    6
    15
    4
    2
    2
    Lymphopenia
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 115 (1.74%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    2 / 26 (7.69%)
         occurrences all number
    5
    2
    1
    0
    3
    4
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    23 / 133 (17.29%)
    18 / 115 (15.65%)
    17 / 82 (20.73%)
    17 / 73 (23.29%)
    6 / 59 (10.17%)
    6 / 26 (23.08%)
         occurrences all number
    32
    21
    25
    19
    8
    8
    Dizziness
         subjects affected / exposed
    17 / 133 (12.78%)
    11 / 115 (9.57%)
    12 / 82 (14.63%)
    11 / 73 (15.07%)
    7 / 59 (11.86%)
    7 / 26 (26.92%)
         occurrences all number
    18
    12
    14
    12
    10
    9
    Headache
         subjects affected / exposed
    10 / 133 (7.52%)
    10 / 115 (8.70%)
    9 / 82 (10.98%)
    11 / 73 (15.07%)
    15 / 59 (25.42%)
    4 / 26 (15.38%)
         occurrences all number
    13
    16
    20
    15
    18
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    16 / 133 (12.03%)
    13 / 115 (11.30%)
    13 / 82 (15.85%)
    4 / 73 (5.48%)
    7 / 59 (11.86%)
    3 / 26 (11.54%)
         occurrences all number
    20
    17
    22
    6
    10
    5
    Paraesthesia
         subjects affected / exposed
    13 / 133 (9.77%)
    12 / 115 (10.43%)
    8 / 82 (9.76%)
    7 / 73 (9.59%)
    8 / 59 (13.56%)
    1 / 26 (3.85%)
         occurrences all number
    19
    20
    10
    11
    9
    2
    Dysgeusia
         subjects affected / exposed
    13 / 133 (9.77%)
    6 / 115 (5.22%)
    12 / 82 (14.63%)
    4 / 73 (5.48%)
    13 / 59 (22.03%)
    0 / 26 (0.00%)
         occurrences all number
    13
    6
    12
    4
    18
    0
    Hypoaesthesia
         subjects affected / exposed
    8 / 133 (6.02%)
    5 / 115 (4.35%)
    1 / 82 (1.22%)
    1 / 73 (1.37%)
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    8
    8
    2
    1
    5
    0
    Polyneuropathy
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    3 / 82 (3.66%)
    2 / 73 (2.74%)
    6 / 59 (10.17%)
    1 / 26 (3.85%)
         occurrences all number
    6
    0
    4
    4
    8
    1
    Tremor
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 115 (1.74%)
    2 / 82 (2.44%)
    1 / 73 (1.37%)
    5 / 59 (8.47%)
    0 / 26 (0.00%)
         occurrences all number
    2
    2
    2
    2
    5
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 133 (0.75%)
    5 / 115 (4.35%)
    4 / 82 (4.88%)
    2 / 73 (2.74%)
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    1
    6
    4
    3
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    41 / 133 (30.83%)
    19 / 115 (16.52%)
    44 / 82 (53.66%)
    28 / 73 (38.36%)
    29 / 59 (49.15%)
    9 / 26 (34.62%)
         occurrences all number
    85
    28
    120
    39
    48
    11
    Nausea
         subjects affected / exposed
    35 / 133 (26.32%)
    29 / 115 (25.22%)
    46 / 82 (56.10%)
    23 / 73 (31.51%)
    25 / 59 (42.37%)
    6 / 26 (23.08%)
         occurrences all number
    59
    45
    96
    33
    34
    9
    Vomiting
         subjects affected / exposed
    27 / 133 (20.30%)
    15 / 115 (13.04%)
    28 / 82 (34.15%)
    18 / 73 (24.66%)
    16 / 59 (27.12%)
    4 / 26 (15.38%)
         occurrences all number
    41
    20
    63
    30
    27
    4
    Constipation
         subjects affected / exposed
    19 / 133 (14.29%)
    22 / 115 (19.13%)
    19 / 82 (23.17%)
    21 / 73 (28.77%)
    14 / 59 (23.73%)
    9 / 26 (34.62%)
         occurrences all number
    22
    32
    24
    27
    17
    9
    Abdominal pain
         subjects affected / exposed
    9 / 133 (6.77%)
    3 / 115 (2.61%)
    9 / 82 (10.98%)
    9 / 73 (12.33%)
    3 / 59 (5.08%)
    4 / 26 (15.38%)
         occurrences all number
    10
    3
    26
    12
    3
    5
    Abdominal pain upper
         subjects affected / exposed
    7 / 133 (5.26%)
    5 / 115 (4.35%)
    9 / 82 (10.98%)
    8 / 73 (10.96%)
    6 / 59 (10.17%)
    2 / 26 (7.69%)
         occurrences all number
    8
    5
    10
    9
    6
    2
    Stomatitis
         subjects affected / exposed
    11 / 133 (8.27%)
    2 / 115 (1.74%)
    11 / 82 (13.41%)
    3 / 73 (4.11%)
    8 / 59 (13.56%)
    2 / 26 (7.69%)
         occurrences all number
    13
    2
    15
    5
    11
    7
    Dyspepsia
         subjects affected / exposed
    7 / 133 (5.26%)
    5 / 115 (4.35%)
    8 / 82 (9.76%)
    6 / 73 (8.22%)
    5 / 59 (8.47%)
    3 / 26 (11.54%)
         occurrences all number
    13
    5
    8
    7
    13
    3
    Dysphagia
         subjects affected / exposed
    5 / 133 (3.76%)
    2 / 115 (1.74%)
    6 / 82 (7.32%)
    2 / 73 (2.74%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    5
    3
    6
    2
    3
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    5 / 82 (6.10%)
    1 / 73 (1.37%)
    1 / 59 (1.69%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    7
    1
    1
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    0 / 59 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    5 / 82 (6.10%)
    5 / 73 (6.85%)
    4 / 59 (6.78%)
    4 / 26 (15.38%)
         occurrences all number
    0
    0
    8
    15
    7
    4
    Renal failure
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    0 / 59 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    0
    0
    1
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    42 / 133 (31.58%)
    43 / 115 (37.39%)
    34 / 82 (41.46%)
    27 / 73 (36.99%)
    14 / 59 (23.73%)
    10 / 26 (38.46%)
         occurrences all number
    51
    48
    47
    34
    19
    11
    Pruritus
         subjects affected / exposed
    14 / 133 (10.53%)
    6 / 115 (5.22%)
    14 / 82 (17.07%)
    10 / 73 (13.70%)
    6 / 59 (10.17%)
    2 / 26 (7.69%)
         occurrences all number
    19
    6
    18
    11
    7
    2
    Rash maculo-papular
         subjects affected / exposed
    18 / 133 (13.53%)
    3 / 115 (2.61%)
    14 / 82 (17.07%)
    4 / 73 (5.48%)
    8 / 59 (13.56%)
    0 / 26 (0.00%)
         occurrences all number
    45
    4
    31
    9
    19
    0
    Dry skin
         subjects affected / exposed
    7 / 133 (5.26%)
    3 / 115 (2.61%)
    13 / 82 (15.85%)
    4 / 73 (5.48%)
    5 / 59 (8.47%)
    2 / 26 (7.69%)
         occurrences all number
    7
    3
    17
    4
    5
    2
    Rash macular
         subjects affected / exposed
    11 / 133 (8.27%)
    0 / 115 (0.00%)
    13 / 82 (15.85%)
    1 / 73 (1.37%)
    5 / 59 (8.47%)
    2 / 26 (7.69%)
         occurrences all number
    14
    0
    16
    1
    9
    2
    Rash papular
         subjects affected / exposed
    13 / 133 (9.77%)
    3 / 115 (2.61%)
    7 / 82 (8.54%)
    0 / 73 (0.00%)
    4 / 59 (6.78%)
    2 / 26 (7.69%)
         occurrences all number
    16
    3
    12
    0
    6
    2
    Erythema
         subjects affected / exposed
    8 / 133 (6.02%)
    2 / 115 (1.74%)
    6 / 82 (7.32%)
    4 / 73 (5.48%)
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    9
    2
    6
    5
    4
    0
    Rash
         subjects affected / exposed
    6 / 133 (4.51%)
    1 / 115 (0.87%)
    3 / 82 (3.66%)
    2 / 73 (2.74%)
    9 / 59 (15.25%)
    1 / 26 (3.85%)
         occurrences all number
    8
    1
    4
    2
    11
    1
    Decubitus ulcer
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 115 (1.74%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    0
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 133 (19.55%)
    22 / 115 (19.13%)
    21 / 82 (25.61%)
    12 / 73 (16.44%)
    15 / 59 (25.42%)
    6 / 26 (23.08%)
         occurrences all number
    33
    35
    28
    21
    16
    9
    Myalgia
         subjects affected / exposed
    13 / 133 (9.77%)
    15 / 115 (13.04%)
    13 / 82 (15.85%)
    6 / 73 (8.22%)
    8 / 59 (13.56%)
    5 / 26 (19.23%)
         occurrences all number
    17
    15
    16
    15
    9
    6
    Pain in extremity
         subjects affected / exposed
    17 / 133 (12.78%)
    9 / 115 (7.83%)
    11 / 82 (13.41%)
    9 / 73 (12.33%)
    11 / 59 (18.64%)
    1 / 26 (3.85%)
         occurrences all number
    29
    14
    13
    13
    17
    2
    Back pain
         subjects affected / exposed
    6 / 133 (4.51%)
    9 / 115 (7.83%)
    14 / 82 (17.07%)
    9 / 73 (12.33%)
    5 / 59 (8.47%)
    4 / 26 (15.38%)
         occurrences all number
    6
    9
    18
    11
    6
    9
    Musculoskeletal pain
         subjects affected / exposed
    5 / 133 (3.76%)
    3 / 115 (2.61%)
    12 / 82 (14.63%)
    5 / 73 (6.85%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    5
    3
    14
    6
    3
    0
    Bone pain
         subjects affected / exposed
    4 / 133 (3.01%)
    4 / 115 (3.48%)
    5 / 82 (6.10%)
    7 / 73 (9.59%)
    5 / 59 (8.47%)
    2 / 26 (7.69%)
         occurrences all number
    5
    8
    6
    12
    5
    4
    Muscular weakness
         subjects affected / exposed
    4 / 133 (3.01%)
    5 / 115 (4.35%)
    4 / 82 (4.88%)
    1 / 73 (1.37%)
    6 / 59 (10.17%)
    3 / 26 (11.54%)
         occurrences all number
    5
    5
    7
    3
    9
    3
    Neck pain
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 115 (0.87%)
    2 / 82 (2.44%)
    5 / 73 (6.85%)
    0 / 59 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    2
    5
    0
    0
    Pain in jaw
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 115 (0.00%)
    0 / 82 (0.00%)
    1 / 73 (1.37%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    1
    4
    0
    Groin pain
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 115 (0.00%)
    1 / 82 (1.22%)
    0 / 73 (0.00%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 133 (21.80%)
    20 / 115 (17.39%)
    29 / 82 (35.37%)
    16 / 73 (21.92%)
    23 / 59 (38.98%)
    11 / 26 (42.31%)
         occurrences all number
    34
    27
    36
    16
    32
    14
    Dehydration
         subjects affected / exposed
    8 / 133 (6.02%)
    12 / 115 (10.43%)
    8 / 82 (9.76%)
    7 / 73 (9.59%)
    10 / 59 (16.95%)
    4 / 26 (15.38%)
         occurrences all number
    10
    16
    8
    10
    17
    7
    Hyperglycaemia
         subjects affected / exposed
    16 / 133 (12.03%)
    14 / 115 (12.17%)
    6 / 82 (7.32%)
    1 / 73 (1.37%)
    6 / 59 (10.17%)
    4 / 26 (15.38%)
         occurrences all number
    26
    23
    16
    1
    15
    8
    Hypomagnesaemia
         subjects affected / exposed
    10 / 133 (7.52%)
    5 / 115 (4.35%)
    5 / 82 (6.10%)
    2 / 73 (2.74%)
    8 / 59 (13.56%)
    0 / 26 (0.00%)
         occurrences all number
    11
    5
    8
    2
    10
    0
    Hypokalaemia
         subjects affected / exposed
    9 / 133 (6.77%)
    3 / 115 (2.61%)
    7 / 82 (8.54%)
    3 / 73 (4.11%)
    5 / 59 (8.47%)
    2 / 26 (7.69%)
         occurrences all number
    14
    4
    12
    3
    8
    2
    Hyponatraemia
         subjects affected / exposed
    5 / 133 (3.76%)
    3 / 115 (2.61%)
    3 / 82 (3.66%)
    4 / 73 (5.48%)
    2 / 59 (3.39%)
    3 / 26 (11.54%)
         occurrences all number
    6
    4
    5
    4
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 115 (0.00%)
    3 / 82 (3.66%)
    2 / 73 (2.74%)
    1 / 59 (1.69%)
    2 / 26 (7.69%)
         occurrences all number
    3
    0
    4
    2
    1
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 133 (3.01%)
    4 / 115 (3.48%)
    11 / 82 (13.41%)
    3 / 73 (4.11%)
    7 / 59 (11.86%)
    0 / 26 (0.00%)
         occurrences all number
    4
    4
    13
    3
    11
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 133 (0.75%)
    3 / 115 (2.61%)
    4 / 82 (4.88%)
    4 / 73 (5.48%)
    6 / 59 (10.17%)
    4 / 26 (15.38%)
         occurrences all number
    1
    3
    4
    5
    7
    5
    Bronchitis
         subjects affected / exposed
    4 / 133 (3.01%)
    5 / 115 (4.35%)
    3 / 82 (3.66%)
    3 / 73 (4.11%)
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    5
    6
    8
    3
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 133 (3.01%)
    4 / 115 (3.48%)
    4 / 82 (4.88%)
    0 / 73 (0.00%)
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    5
    4
    5
    0
    4
    0
    Rhinitis
         subjects affected / exposed
    3 / 133 (2.26%)
    0 / 115 (0.00%)
    5 / 82 (6.10%)
    2 / 73 (2.74%)
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    7
    2
    5
    0
    Pneumonia
         subjects affected / exposed
    5 / 133 (3.76%)
    4 / 115 (3.48%)
    0 / 82 (0.00%)
    0 / 73 (0.00%)
    1 / 59 (1.69%)
    2 / 26 (7.69%)
         occurrences all number
    5
    4
    0
    0
    1
    2
    Sinusitis
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 115 (0.87%)
    4 / 82 (4.88%)
    0 / 73 (0.00%)
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    4
    0
    3
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Feb 2012
    One inclusion criterion was modified to require all subjects to continue the use of contraception for 6 months after the last dose of paclitaxel and the duration of follow-up of female patients for pregnancy events was modified to be consistent with the use of contraception for 6 months after paclitaxel exposure. The schedule of assessments was changed to add pregnancy testing of female patients of childbearing potential prior to each cycle of study treatment. A criterion was added to exclude subjects with active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation such as Crohn's disease or ulcerative colitis. The contraindication of therapeutic warfarin use with GDC-0941 and bevacizumab has been removed from the exclusion criterion and the list of excluded medications.
    15 Jan 2013
    The study design was modified to include the evaluation of pictilisib at a dose of 260 mg in subjects with non-squamous NSCLC. The risks associated with pictilisib was updated with new safety information. Modifications to the Inclusion/Exclusion criteria were added: 1) subjects with a history of carcinoma in situ were to be allowed to enroll in study, 2) exclusion of subjects with epidermal growth factor receptor (EGFR) mutation was limited to those whose mutation is associated with response to tyrosine kinase inhibitors. Triplicate 12-lead electrocardiogram (ECG) assessments were replaced with single 12-lead ECGs. Subjects with the following adverse events (AEs) of special interest were to be monitored and evaluated closely for their response to clinical intervention: Grade 4 or symptomatic Grade 3 hyperglycemia, Grade 3 rash, or Grade 2 pneumonitis. The statistical methods were modified to reflect the changes to the study design.
    19 Dec 2013
    In order to have sufficient number of subjects to assess PFS in the PIK3CA amplified subgroup (co-primary endpoint), the total number of subjects in Arms A and B was increased from 146 to approximately 250 subjects with squamous NSCLC to take into account a higher percentage of subject tumor samples being unevaluable with the phosphoinositide 3-kinase (PI3K) fluorescence in situ hybridisation (FISH) assay. Further clarification around exclusion criteria was provided as follows: Exclusion: Active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation, such as Crohn’s or ulcerative colitis. Subjects receiving immunosuppressants were considered to have active disease and were not allowed.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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