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    Clinical Trial Results:
    Neo- / adjuvant phase III trial to compare intense dose-dense chemotherapy to tailored dose-dense chemotherapy in patients with high-risk early breast cancer (GAIN-2 trial)

    Summary
    EudraCT number
    		 2011-005214-11
    Trial protocol
    		 DE  
    Global end of trial date
    07 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Oct 2021
    First version publication date
    27 Oct 2021
    Other versions
    Summary report(s)
    		 GAIN-2 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    GBG-68
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01690702
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 no: no
    Sponsors
    Sponsor organisation name
    GBG Forschungs GmbH
    Sponsor organisation address
    Martin-Behaim-Straße 12, Neu-Isenburg, Germany,
    Public contact
    Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de
    Scientific contact
    Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de
    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
    15 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the invasive disease-free survival (IDFS) after neo- / adjuvant chemotherapy with EnPC or dtEC-dtD in patients with early node-positive or high-risk node-negative breast cancer.
    Protection of trial subjects
    The trial protocol including amendments, the patient information and the informed consent were reviewed and approved from a properly constituted IRB/IEC for each site prior to the study start. The trial was in compliance with the International Conference on Harmonization (ICH) - Harmonized Tripartite Guideline for Good Clinical Practice (GCP) (E6), and the Commission Directives in the European Community as well as with the applicable German national laws and regulations, and with Declaration of Helsinki and its revisions in all aspects of preparation, monitoring, reporting, auditing, and archiving. IDMC was to ensure the ethical conduct of the trial and to protect patients' safety interests in this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 2857
    Worldwide total number of subjects
    2857
    EEA total number of subjects
    2857
    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)
    2698
    From 65 to 84 years
    159
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 5 years (Q-IV 2012 –Q-III 2017) in 136 sites in Germany. 2887 patients were randomized, 2857 patients started treatment (iddEnPC 1429; dtEC-dtD 1428).

    Pre-assignment
    Screening details
    		 Female patients <18 - 70years, uni- or bilateral primary BC, Karnofsky index ≥ 80%, estimated life expectancy of >=10 years irresp. of BC. Centrally confirmed ER, PgR , HER2, and Ki-67 on surgical or core biopsy eligible. High risk BC defined as HER2+ or TNBC irresp. of nodal status or luminal B-like with N+ or luminal A-like with >=4 involved LN

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EnPC
    Arm description
    		 • intense dose-dense epirubicin for 3 cycles followed by • intense dose-dense nab-paclitaxel for 3 cycles followed by • intense dose-dense cyclophosphamide for 3 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered i.v. over 20 min via catheter to the subclavian vein or an implanted port system. The schedule of administration was 150 mg/m² (EnPC) given on day 1 every 2 weeks for 3 cycles (EnPC).

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered i.v. over 120 min (EnPC) . The schedule of administration was 2000 mg/m² (EnPC) given on day 1 every 2 weeks for 3 cycles (EnPC).

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    nab-paclitaxel was administered i.v. over 30-60 min. The schedule of administration was 330 mg/m² (after determination during the run-in phase) given on day 1 q day 14 for 3 cycles

    Arm title
    		 dtEC-dtD
    Arm description
    		 • dose-dense / dose-tailored epirubicin / cyclophosphamide for 4 cycles followed after 1 additional week of rest by • dose-dense / dose-tailored docetaxel for 4 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered i.v. over 20 min via catheter to the subclavian vein or an implanted port system. The schedule of administration was 38-120 mg/m² (dtEC-dtD) given on day 1 every 2 weeks for 4 cycles (dtEC-dtD).

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered i.v. over 60 min. The schedule of administration was 60-100 mg/m² (dtEC-dtD) given on day 1 every 2 weeks for 4 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered i.v. over 60 min (dtEC-dtD). The schedule of administration was 450-1200 mg/m² (dtEC-dtD) given on day 1 every 2 weeks for 4 cycles (dtEC-dtD).

    Number of subjects in period 1
    		EnPC dtEC-dtD
    Started
    1429
    1428
    Completed
    1259
    1258
    Not completed
    170
    170
         Physician decision
    24
    23
         Consent withdrawn by subject
    48
    47
         death
    -
    2
         Adverse event, non-fatal
    94
    91
         local progression
    2
    2
         relapse
    2
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EnPC
    Reporting group description
    		 • intense dose-dense epirubicin for 3 cycles followed by • intense dose-dense nab-paclitaxel for 3 cycles followed by • intense dose-dense cyclophosphamide for 3 cycles.

    Reporting group title
    dtEC-dtD
    Reporting group description
    		 • dose-dense / dose-tailored epirubicin / cyclophosphamide for 4 cycles followed after 1 additional week of rest by • dose-dense / dose-tailored docetaxel for 4 cycles.

    Reporting group values
    		 EnPC dtEC-dtD Total
    Number of subjects
    		 1429 1428 2857
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 51 (18 to 73) 51 (20 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 1429 1428 2857
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    EnPC
    Reporting group description
    		 • intense dose-dense epirubicin for 3 cycles followed by • intense dose-dense nab-paclitaxel for 3 cycles followed by • intense dose-dense cyclophosphamide for 3 cycles.

    Reporting group title
    dtEC-dtD
    Reporting group description
    		 • dose-dense / dose-tailored epirubicin / cyclophosphamide for 4 cycles followed after 1 additional week of rest by • dose-dense / dose-tailored docetaxel for 4 cycles.

    Primary: iDFS rate

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    End point title
    		 iDFS rate
    End point description
    iDFS rate at 48months follow up
    End point type
    Primary
    End point timeframe
    iDFS defined as the time period between randomization and first event (local, loco-regional or distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, second primary invasive cancer [non-breast])
    End point values
    		 EnPC dtEC-dtD
    Number of subjects analysed
    1429
    1428
    Units: percent
        number (confidence interval 95%)
    84.3 (82.0 to 86.4)
    84.3 (82.0 to 86.4)
    Statistical analysis title
    		 Hazard ratio
    Comparison groups
    EnPC v dtEC-dtD
    Number of subjects included in analysis
    2857
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.23
    Notes
    [1] - The non-inferiority margin of 5% prespecified in the protocol was crossed, i.e. the 95%-CI for hazard ratio excluded 1.05. Therefore, the non-inferiority could not be shown.
    Statistical analysis title
    		 Two-sided log-rank
    Statistical analysis description
    The difference in iDFS time was tested using a two-sided log-rank test with significance level of α = 0.05.
    Comparison groups
    EnPC v dtEC-dtD
    Number of subjects included in analysis
    2857
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.9102 [3]
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - A closed test procedure was used to test for non-inferiority and superiority.
    [3] - The 4-year iDFS rate was identical in both arms with 84.3% (95% CI 82.0% to 86.4%) and a log-rank p=0.9102

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring during the study treatment period were reported.
    Adverse event reporting additional description
    Non-serious AEs are reported per patient; any grade (1-4) during the complete treatment duration for the overall safety population. Free-text AEs are listed if occurring in >20% Note, overall number of single AE occurrences per term was not assessed, only per Patient. AEs reported as free text are not shown.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    EnPC
    Reporting group description
    		 Analysis of safety and compliance to treatment was performed based on patients who were randomized and received at least once study treatment (2857 patients). For safety and compliance, patients were analyzed according to the treatment which they actually received. One patient randomized to the dtEC-dtD arm was treated in the EnPC arm and was therefore analyzed in the EnPC arm in all safety analyses (safety set: EnPC: 1430 patients; dtEC-dtD: 1427 patients.

    Reporting group title
    dtEC-dtD
    Reporting group description
    		 Analysis of safety and compliance to treatment was performed based on patients who were randomized and received at least once study treatment (2857 patients). For safety and compliance, patients were analyzed according to the treatment which they actually received. One patient randomized to the dtEC-dtD arm was treated in the EnPC arm and was therefore analyzed in the EnPC arm in all safety analyses (safety set: EnPC: 1430 patients; dtEC-dtD: 1427 patients.

    Serious adverse events
    		 EnPC dtEC-dtD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    546 / 1430 (38.18%)
    394 / 1427 (27.61%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    5 / 1430 (0.35%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 1430 (0.14%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site thrombosis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    10 / 1430 (0.70%)
    7 / 1427 (0.49%)
         occurrences causally related to treatment / all
    9 / 10
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    10 / 1430 (0.70%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    7 / 10
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Administration site extravasation
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site extravasation
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site inflammation
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site thrombosis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 1430 (0.00%)
    4 / 1427 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 1430 (0.07%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    2 / 1430 (0.14%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    3 / 1430 (0.21%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    19 / 1430 (1.33%)
    17 / 1427 (1.19%)
         occurrences causally related to treatment / all
    19 / 19
    17 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    42 / 1430 (2.94%)
    25 / 1427 (1.75%)
         occurrences causally related to treatment / all
    40 / 42
    25 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion device issue
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 1430 (0.21%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    7 / 1430 (0.49%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    7 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 1430 (0.00%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    7 / 1430 (0.49%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    7 / 7
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    60 / 1430 (4.20%)
    54 / 1427 (3.78%)
         occurrences causally related to treatment / all
    59 / 60
    49 / 54
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Swelling
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic pain
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 1430 (0.07%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Alveolitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 1430 (0.07%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 1430 (0.49%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    6 / 7
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 1430 (0.14%)
    4 / 1427 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal inflammation
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed anxiety and depressed mood
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    3 / 1430 (0.21%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 1430 (0.14%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 1430 (0.07%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 1430 (0.07%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    3 / 1430 (0.21%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 1430 (0.07%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic hyperglycaemic coma
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 1430 (0.35%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 1430 (0.14%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 1430 (0.14%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 1430 (0.28%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    3 / 1430 (0.21%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 1430 (0.28%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    19 / 1430 (1.33%)
    11 / 1427 (0.77%)
         occurrences causally related to treatment / all
    19 / 19
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    143 / 1430 (10.00%)
    49 / 1427 (3.43%)
         occurrences causally related to treatment / all
    143 / 143
    49 / 49
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    3 / 1430 (0.21%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    55 / 1430 (3.85%)
    42 / 1427 (2.94%)
         occurrences causally related to treatment / all
    55 / 55
    42 / 42
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    119 / 1430 (8.32%)
    50 / 1427 (3.50%)
         occurrences causally related to treatment / all
    119 / 119
    50 / 50
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    5 / 1430 (0.35%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    26 / 1430 (1.82%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    26 / 26
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    12 / 1430 (0.84%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    12 / 12
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    3 / 1430 (0.21%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inner ear disorder
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    5 / 1430 (0.35%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye inflammation
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 1430 (0.21%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 1430 (0.21%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    2 / 1430 (0.14%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    5 / 1430 (0.35%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    18 / 1430 (1.26%)
    14 / 1427 (0.98%)
         occurrences causally related to treatment / all
    18 / 18
    13 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    5 / 1430 (0.35%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    21 / 1430 (1.47%)
    9 / 1427 (0.63%)
         occurrences causally related to treatment / all
    21 / 21
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 1430 (0.14%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    5 / 1430 (0.35%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    22 / 1430 (1.54%)
    20 / 1427 (1.40%)
         occurrences causally related to treatment / all
    22 / 22
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder necrosis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis chronic active
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutis laxa
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epidermolysis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 1430 (0.00%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 1430 (0.00%)
    7 / 1427 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin reaction
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 1430 (0.21%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 1430 (0.14%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 1430 (0.14%)
    4 / 1427 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    6 / 1430 (0.42%)
    9 / 1427 (0.63%)
         occurrences causally related to treatment / all
    4 / 6
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Myalgia
         subjects affected / exposed
    2 / 1430 (0.14%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 1430 (0.07%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    5 / 1430 (0.35%)
    5 / 1427 (0.35%)
         occurrences causally related to treatment / all
    1 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 1430 (0.14%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    2 / 1430 (0.14%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 1430 (0.00%)
    157 / 1427 (11.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    5 / 1430 (0.35%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    3 / 1430 (0.21%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    10 / 1430 (0.70%)
    12 / 1427 (0.84%)
         occurrences causally related to treatment / all
    9 / 10
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    5 / 1430 (0.35%)
    3 / 1427 (0.21%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site infection
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    5 / 1430 (0.35%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail infection
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 1430 (0.98%)
    19 / 1427 (1.33%)
         occurrences causally related to treatment / all
    9 / 14
    19 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 1430 (0.21%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 1430 (0.21%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urogenital infection bacterial
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 1430 (0.14%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    3 / 1430 (0.21%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 1430 (0.07%)
    0 / 1427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 1430 (0.07%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 1430 (0.00%)
    1 / 1427 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1430 (0.00%)
    2 / 1427 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EnPC dtEC-dtD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1429 / 1430 (99.93%)
    1426 / 1427 (99.93%)
    Investigations
    Alanine aminotransferase increased
    Additional description: ALAT increased
         subjects affected / exposed
    977 / 1430 (68.32%)
    842 / 1427 (59.00%)
         occurrences all number
    977
    842
    Aspartate aminotransferase increased
    Additional description: ASAT increased
         subjects affected / exposed
    628 / 1430 (43.92%)
    526 / 1427 (36.86%)
         occurrences all number
    628
    526
    Blood bilirubin increased
         subjects affected / exposed
    73 / 1430 (5.10%)
    63 / 1427 (4.41%)
         occurrences all number
    73
    63
    Blood creatinine increased
         subjects affected / exposed
    168 / 1430 (11.75%)
    164 / 1427 (11.49%)
         occurrences all number
    168
    164
    Vascular disorders
    Embolism
         subjects affected / exposed
    60 / 1430 (4.20%)
    61 / 1427 (4.27%)
         occurrences all number
    60
    61
    Epistaxis
         subjects affected / exposed
    149 / 1430 (10.42%)
    362 / 1427 (25.37%)
         occurrences all number
    149
    362
    Hypertension
         subjects affected / exposed
    165 / 1430 (11.54%)
    140 / 1427 (9.81%)
         occurrences all number
    165
    140
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    8 / 1430 (0.56%)
    7 / 1427 (0.49%)
         occurrences all number
    8
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    432 / 1430 (30.21%)
    491 / 1427 (34.41%)
         occurrences all number
    432
    491
    Peripheral sensory neuropathy
         subjects affected / exposed
    1190 / 1430 (83.22%)
    903 / 1427 (63.28%)
         occurrences all number
    1190
    903
    Dysgeusia
    Additional description: reported as free-text
         subjects affected / exposed
    320 / 1430 (22.38%)
    387 / 1427 (27.12%)
         occurrences all number
    320
    387
    Blood and lymphatic system disorders
    Blood alkaline phosphatase increased
    Additional description: Blood AP increased
         subjects affected / exposed
    847 / 1430 (59.23%)
    629 / 1427 (44.08%)
         occurrences all number
    847
    629
    Anaemia
         subjects affected / exposed
    1410 / 1430 (98.60%)
    1408 / 1427 (98.67%)
         occurrences all number
    1410
    1408
    Leukopenia
         subjects affected / exposed
    1411 / 1430 (98.67%)
    1401 / 1427 (98.18%)
         occurrences all number
    1411
    1401
    Lymphopenia
         subjects affected / exposed
    1389 / 1430 (97.13%)
    1389 / 1427 (97.34%)
         occurrences all number
    1389
    1389
    Neutropenia
         subjects affected / exposed
    1350 / 1430 (94.41%)
    1308 / 1427 (91.66%)
         occurrences all number
    1350
    1308
    Thrombocytopenia
         subjects affected / exposed
    1250 / 1430 (87.41%)
    1041 / 1427 (72.95%)
         occurrences all number
    1250
    1041
    General disorders and administration site conditions
    Febrile neutropenia
         subjects affected / exposed
    174 / 1430 (12.17%)
    73 / 1427 (5.12%)
         occurrences all number
    174
    73
    Decreased appetite
         subjects affected / exposed
    353 / 1430 (24.69%)
    299 / 1427 (20.95%)
         occurrences all number
    353
    299
    Fatigue
         subjects affected / exposed
    1210 / 1430 (84.62%)
    1220 / 1427 (85.49%)
         occurrences all number
    1210
    1220
    Mucosal inflammation
         subjects affected / exposed
    958 / 1430 (66.99%)
    968 / 1427 (67.83%)
         occurrences all number
    958
    968
    Pyrexia
         subjects affected / exposed
    255 / 1430 (17.83%)
    274 / 1427 (19.20%)
         occurrences all number
    255
    274
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    168 / 1430 (11.75%)
    193 / 1427 (13.52%)
         occurrences all number
    168
    193
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    539 / 1430 (37.69%)
    561 / 1427 (39.31%)
         occurrences all number
    539
    561
    Nausea
         subjects affected / exposed
    1057 / 1430 (73.92%)
    1055 / 1427 (73.93%)
         occurrences all number
    1057
    1055
    Vomiting
         subjects affected / exposed
    390 / 1430 (27.27%)
    322 / 1427 (22.56%)
         occurrences all number
    390
    322
    Constipation
    Additional description: reported as free-text
         subjects affected / exposed
    544 / 1430 (38.04%)
    451 / 1427 (31.60%)
         occurrences all number
    544
    451
    Other gastrointestinal disorders
    Additional description: reported as free-text
         subjects affected / exposed
    338 / 1430 (23.64%)
    361 / 1427 (25.30%)
         occurrences all number
    338
    361
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    297 / 1430 (20.77%)
    341 / 1427 (23.90%)
         occurrences all number
    297
    341
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1313 / 1430 (91.82%)
    1318 / 1427 (92.36%)
         occurrences all number
    1313
    1318
    Nail disorder
    Additional description: reported as free-text
         subjects affected / exposed
    331 / 1430 (23.15%)
    286 / 1427 (20.04%)
         occurrences all number
    331
    286
    Other skin and subcutaneous tissue disorder
    Additional description: reported as free-text
         subjects affected / exposed
    380 / 1430 (26.57%)
    417 / 1427 (29.22%)
         occurrences all number
    380
    417
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    836 / 1430 (58.46%)
    639 / 1427 (44.78%)
         occurrences all number
    836
    639
    Myalgia
         subjects affected / exposed
    642 / 1430 (44.90%)
    533 / 1427 (37.35%)
         occurrences all number
    642
    533
    Infections and infestations
    Infection
         subjects affected / exposed
    384 / 1430 (26.85%)
    408 / 1427 (28.59%)
         occurrences all number
    384
    408
    Other infections and infestations
    Additional description: reported as free-text
         subjects affected / exposed
    311 / 1430 (21.75%)
    280 / 1427 (19.62%)
         occurrences all number
    311
    280

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2012
    The study protocol was amended to implement a change in the inclusion criteria. The definition of high risk breast cancer was expanded to also include patients with luminal A like tumors and 4 or more involved lymph nodes.
    19 Dec 2012
    The study protocol and informed consent form (ICF) were amended to implement changes in the design of the run-in phase. The number of patients additionally recruited into each dose-level to avoid interruption of accrual was increased from 10 to 20.
    28 Apr 2016
    Amendment 3 was a substantial amendment of the study protocol and ICF to open GAIN-2 for the neoadjuvant setting due to slow accrual. While endpoints of the study remained unchanged, an additional stratification factor was added (neoadjuvant vs adjuvant chemotherapy) and HER2-positive patients were now allowed to receive dual anti-HER2-blockade (Pertuzumab + Trastuzumab). Corresponding changes were implemented in all parts of the protocol.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34450552
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