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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label, Phase III Trial Comparing Trastuzumab Plus Pertuzumab Plus a Taxane Following Anthracyclines Versus Trastuzumab Emtansine Plus Pertuzumab Following Anthracyclines as Adjuvant Therapy in Patients with Operable HER2-Positive Primary Breast Cancer

    Summary
    EudraCT number
    		 2012-004902-82
    Trial protocol
    		 IT   GB   HU   DE   CZ   ES   NO   BE   SE   PL   FR  
    Global end of trial date
    04 Jun 2021

    Results information
    Results version number
    		 v3(current)
    This version publication date
    22 May 2022
    First version publication date
    05 Dec 2020
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BO28407
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01966471
    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
    04 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare invasive disease-free survival (IDFS) in the node-positive subpopulation and in the overall protocol-defined population of patients with HER2-positive breast cancer randomized to receive either, a taxane and one year of trastuzumab plus pertuzumab following anthracycline-based chemotherapy or one year of trastuzumab emtansine plus pertuzumab following anthracycline-based chemotherapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 Anthracycline followed by Trastuzumab, Pertuzumab, and Taxane was selected as the comparator for this study based on data from other clinical trials.
    Actual start date of recruitment
    31 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 7 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 46
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 13
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Canada: 107
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Czechia: 35
    Country: Number of subjects enrolled
    El Salvador: 10
    Country: Number of subjects enrolled
    France: 81
    Country: Number of subjects enrolled
    Georgia: 37
    Country: Number of subjects enrolled
    Germany: 119
    Country: Number of subjects enrolled
    Guatemala: 10
    Country: Number of subjects enrolled
    Hong Kong: 16
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 130
    Country: Number of subjects enrolled
    Japan: 260
    Country: Number of subjects enrolled
    Korea, Republic of: 90
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Panama: 12
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Philippines: 9
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Russian Federation: 95
    Country: Number of subjects enrolled
    Singapore: 21
    Country: Number of subjects enrolled
    Spain: 69
    Country: Number of subjects enrolled
    Sweden: 21
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    Taiwan: 88
    Country: Number of subjects enrolled
    Thailand: 24
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    United Kingdom: 124
    Country: Number of subjects enrolled
    United States: 148
    Worldwide total number of subjects
    1846
    EEA total number of subjects
    630
    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)
    1595
    From 65 to 84 years
    251
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 288 centers in 36 countries.

    Pre-assignment
    Screening details
    		 Randomization was stratified according to geographic region, nodal status, centrally assessed hormonal receptor status and type of anthracycline. A total of 1846 subjects were enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Arm description
    		 Trastuzumab and pertuzumab were administered concurrently for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    An IV infusion (duration 90 minutes) was administered at 8 mg/kg loading dose followed by 6 mg/kg IV q3w for up to 18 cycles (1 cycle = 21 days).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    An IV infusion of paclitaxel 80 mg/m^2 once weekly may be administered concurrently with trastuzumab in combination with pertuzumab for 12 weeks.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion either docetaxel every 3 weeks (q3w) (at 100 milligram per square meter [mg/m^2] for 3 cycles (1 cycle = 21 days); at 75 mg/m2 for 4 cycles; or start at 75 mg/m^2 in the first cycle and escalate to 100 mg/m^2 if no dose limiting toxicity occurs, for a total of 3 cycles at minimum) may be administered concurrently with trastuzumab in combination with pertuzumab.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using cyclophosphamide (FEC) may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    An infusion (duration 60 minutes) was administered at 840 mg loading dose followed by 420 mg IV q3w for up to 18 cycles (1 cycle = 21 days).

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using doxorubicin may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Arm title
    		 Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Arm description
    		 Trastuzumab emtansine and pertuzumab continued for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    Other name
    Kadcyla
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    An intravenous (IV) infusion (duration 90 minutes) was administered at 3.6 milligram per kilogram (mg/kg) every three weeks (q3w) for up to 18 cycles (1 cycle = 21 days).

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    An infusion (duration 60 minutes) was administered at 840 mg loading dose followed by 420 mg IV q3w for up to 18 cycles (1 cycle = 21 days).

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using doxorubicin may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using cyclophosphamide (FEC) may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both treatment arms as per discretion of the investigator and local prescribing information/institutional guidelines.

    Number of subjects in period 1
    		Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Started
    918
    928
    Completed
    0
    0
    Not completed
    918
    928
         Physician decision
    7
    5
         Withdrawal By Subject
    59
    51
         Study Terminated By Sponsor
    758
    773
         Death
    44
    56
         Lost to follow-up
    46
    39
         Various Reasons
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Reporting group description
    		 Trastuzumab and pertuzumab were administered concurrently for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.

    Reporting group title
    Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Reporting group description
    		 Trastuzumab emtansine and pertuzumab continued for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.

    Reporting group values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab Total
    Number of subjects
    		 918 928 1846
    Age Categorical
    Units: Subjects
        Preterm newborn infants(gestational age <37 weeks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 786 809 1595
        From 65-84 years
    		 132 119 251
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.6 ( 10.8 ) 51.9 ( 10.8 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 913 926 1839
        Male
    		 5 2 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 70 68 138
        Not Hispanic or Latino
    		 798 790 1588
        Not Stated
    		 35 44 79
        Unknown
    		 15 26 41
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 12 12 24
        Asian
    		 267 275 542
        Black or African American
    		 15 8 23
        Native Hawaiian or other Pacific Islander
    		 1 1 2
        White
    		 558 565 1123
        Other
    		 30 27 57
        Multiple
    		 2 2 4
        Unknown
    		 33 38 71
    Subject analysis sets

    Subject analysis set title
    AC-THP Node Positive Subpopulation
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The lymph node positive population was a subpopulation of the randomized participant population including patients with positive lymph node.

    Subject analysis set title
    AC-KP Node Positive Subpopulation
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The lymph node positive population was a subpopulation of the randomized participant population including patients with positive lymph node.

    Subject analysis set title
    AC-THP Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized participants who received at least one full or partial dose of any study treatment.

    Subject analysis set title
    AC-KP Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized participants who received at least one full or partial dose of any study treatment.

    Subject analysis sets values
    		 AC-THP Node Positive Subpopulation AC-KP Node Positive Subpopulation AC-THP Safety Population AC-KP Safety Population
    Number of subjects
    826
    832
    926
    912
    Age Categorical
    Units: Subjects
        Preterm newborn infants(gestational age <37 weeks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    708
    728
    792
    797
        From 65-84 years
    118
    104
    134
    115
        85 years and over
    0
    0
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.2 ( 11.0 )
    51.7 ( 10.8 )
    51.6 ( 10.9 )
    51.8 ( 10.8 )
    Sex: Female, Male
    Units: Subjects
        Female
    821
    830
    921
    910
        Male
    5
    2
    5
    2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    66
    60
    71
    67
        Not Hispanic or Latino
    717
    711
    801
    779
        Not Stated
    30
    38
    38
    41
        Unknown
    13
    23
    16
    25
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    11
    11
    12
    12
        Asian
    237
    246
    270
    269
        Black or African American
    15
    8
    14
    8
        Native Hawaiian or other Pacific Islander
    1
    1
    1
    1
        White
    502
    511
    560
    559
        Other
    28
    20
    31
    26
        Multiple
    2
    2
    2
    2
        Unknown
    30
    33
    36
    35

    End points

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    End points reporting groups
    Reporting group title
    Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Reporting group description
    		 Trastuzumab and pertuzumab were administered concurrently for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.

    Reporting group title
    Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Reporting group description
    		 Trastuzumab emtansine and pertuzumab continued for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.

    Subject analysis set title
    AC-THP Node Positive Subpopulation
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The lymph node positive population was a subpopulation of the randomized participant population including patients with positive lymph node.

    Subject analysis set title
    AC-KP Node Positive Subpopulation
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The lymph node positive population was a subpopulation of the randomized participant population including patients with positive lymph node.

    Subject analysis set title
    AC-THP Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized participants who received at least one full or partial dose of any study treatment.

    Subject analysis set title
    AC-KP Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized participants who received at least one full or partial dose of any study treatment.

    Primary: Invasive Disease−Free Survival (IDFS) in the Node-Positive Subpopulation

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    End point title
    		 Invasive Disease−Free Survival (IDFS) in the Node-Positive Subpopulation
    End point description
    IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer [bc] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site [other than the three sites mentioned above]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population was estimated using the Kaplan-Meier method and estimated the probability of a participant being event-free after 3 years after randomization.
    End point type
    Primary
    End point timeframe
    Last participant randomized to data cut-off date of 27 November 2019 (approximately 70 months). The 3 year IDFS event-free rate was assessed based on the data collected for each participant considering the cut-off date mentioned above.
    End point values
    		 AC-THP Node Positive Subpopulation AC-KP Node Positive Subpopulation
    Number of subjects analysed
    826
    832
    Units: Percent Probability
        number (confidence interval 95%)
    94.10 (92.46 to 95.73)
    92.75 (90.95 to 94.54)
    Statistical analysis title
    		 IDFS in the Node-Positive Subpopulation
    Comparison groups
    AC-THP Node Positive Subpopulation v AC-KP Node Positive Subpopulation
    Number of subjects included in analysis
    1658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.827
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.32

    Primary: Invasive Disease-Free Survival (IDFS) in the Overall Population

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    End point title
    		 Invasive Disease-Free Survival (IDFS) in the Overall Population
    End point description
    IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer [bc] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site [other than the three sites mentioned above]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
    End point type
    Primary
    End point timeframe
    First participant randomized up to approximately 7.5 years
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    918
    928
    Units: Percent Probability
        number (confidence interval 95%)
    94.22 (92.68 to 95.76)
    93.06 (91.40 to 94.73)
    Statistical analysis title
    		 IDFS
    Comparison groups
    Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab v Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Number of subjects included in analysis
    1846
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9291
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.34

    Secondary: IDFS Plus Second Primary Non-Breast Cancer

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    End point title
    		 IDFS Plus Second Primary Non-Breast Cancer
    End point description
    IDFS including second primary non-breast cancer was defined the same way as IDFS for the primary endpoint but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ (CIS) of any site).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 70 months
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    918
    928
    Units: Percent Probability
        number (confidence interval 95%)
    93.43 (91.79 to 95.06)
    92.26 (90.51 to 94.02)
    Statistical analysis title
    		 IDFS Plus Second Primary Non-Breast Cancer
    Comparison groups
    Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane v Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects included in analysis
    1846
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8756
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.3

    Secondary: Disease-Free Survival (DFS)

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    End point title
    		 Disease-Free Survival (DFS)
    End point description
    DFS was defined as time between randomization and first occurrence of IDFS, second primary non-breast cancer and contralateral or ipsilateral ductal carcinoma in situ (DCIS).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 70 months
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    918
    928
    Units: Percent Probability
        number (confidence interval 95%)
    92.04 (90.26 to 93.81)
    93.32 (91.67 to 94.97)
    Statistical analysis title
    		 DFS
    Comparison groups
    Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab v Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Number of subjects included in analysis
    1846
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9341
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.31

    Secondary: Distant Recurrence-Free Interval (DRFI)

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    End point title
    		 Distant Recurrence-Free Interval (DRFI)
    End point description
    DRFI was defined as time between randomization and first occurrence of distant breast cancer recurrence.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 70 months
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    918
    928
    Units: Percent Probability
        number (confidence interval 95%)
    95.23 (93.82 to 96.64)
    94.91 (93.46 to 96.36)
    Statistical analysis title
    		 DRFI
    Comparison groups
    Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane v Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects included in analysis
    1846
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4577
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.25

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 7.5 years
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    918
    928
    Units: Percent Probability
        number (confidence interval 95%)
    96.03 (94.72 to 97.34)
    94.86 (93.40 to 96.32)
    Statistical analysis title
    		 OS
    Comparison groups
    Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane v Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects included in analysis
    1846
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2864
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.84

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a participant 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. AEs were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 7.5 years
    End point values
    		 AC-THP Safety Population AC-KP Safety Population
    Number of subjects analysed
    926
    912
    Units: Percentage of participants
        number (not applicable)
    98.5
    99.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Decrease in Left Ventricular Ejection Fraction (LVEF) From Baseline Over Time

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    End point title
    		 Percentage of Participants With Decrease in Left Ventricular Ejection Fraction (LVEF) From Baseline Over Time
    End point description
    LVEF was assessed using either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans. Status 1: Decrease from baseline <10 Ejection Fraction (EF) points (n=506, 522) Status 2: Absolute value >= 50% and decrease from baseline >= 10 EF points (n=254, 245) Status 3: Absolute value < 50% and decrease from baseline >= 10 EF points (n=71, 35) Status 4: Absolute value < 50% and decrease from baseline >= 15 EF points (n=61, 28)
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 7.5 years
    End point values
    		 AC-THP Safety Population AC-KP Safety Population
    Number of subjects analysed
    914
    912
    Units: Percentage of participants
    number (not applicable)
        Status 1 (n=506, 522)
    55.4
    57.2
        Status 2 (n=254, 245)
    27.8
    26.9
        Status 3 (n=71, 35)
    7.8
    3.8
        Status 4 (n=61, 28)
    6.7
    3.1
    No statistical analyses for this end point

    Secondary: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score

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    End point title
    		 European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score
    End point description
    The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 7 - 15 points considered to be a clinically meaningful deterioration to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1). The value '9999999' indicates that the mean and standard deviation were not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 1, 2, 3, 4, 5, 9, 14, End of Treatment, Follow-up Month 6, Follow-up Month 12, Follow-up Month 18
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    869
    891
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline: Appetite Loss
    8.2 ( 17.6 )
    7.6 ( 16.8 )
        Change at Cycle 1: Appetite Loss
    12.2 ( 27.9 )
    10.8 ( 26.6 )
        Change at Cycle 2: Appetite Loss
    15.2 ( 27.7 )
    13.1 ( 26.7 )
        Change at Cycle 3: Appetite Loss
    14.3 ( 28.2 )
    10.3 ( 25.7 )
        Change at Cycle 4: Appetite Loss
    16.2 ( 29.8 )
    9.4 ( 25.5 )
        Change at Cycle 5: Appetite Loss
    12.0 ( 28.4 )
    9.0 ( 26.2 )
        Change at Cycle 9: Appetite Loss
    5.7 ( 23.9 )
    8.2 ( 25.7 )
        Change at Cycle 14: Appetite Loss
    2.2 ( 23.1 )
    6.4 ( 25.4 )
        Change at EoT: Appetite Loss
    0.5 ( 22.3 )
    5.6 ( 25.1 )
        Change at FU Month 6: Appetite Loss
    -1.3 ( 20.7 )
    -2.4 ( 20.3 )
        Change at FU Month 12: Appetite Loss
    -2.2 ( 20.8 )
    -2.3 ( 20.5 )
        Change at FU Month 18: Appetite Loss
    9999999 ( 9999999 )
    -16.7 ( 23.6 )
        Baseline: Constipation
    9.6 ( 19.4 )
    9.0 ( 19.6 )
        Change at Cycle 1: Constipation
    8.4 ( 22.5 )
    8.0 ( 26.1 )
        Change at Cycle 2: Constipation
    1.1 ( 25.0 )
    0.9 ( 23.1 )
        Change at Cycle 3: Constipation
    2.0 ( 24.6 )
    0.2 ( 22.2 )
        Change at Cycle 4: Constipation
    2.5 ( 24.3 )
    -0.6 ( 23.2 )
        Change at Cycle 5: Constipation
    0.5 ( 22.4 )
    -0.4 ( 22.1 )
        Change at Cycle 9: Constipation
    -0.7 ( 21.7 )
    3.3 ( 24.7 )
        Change at Cycle 14: Constipation
    0.6 ( 21.1 )
    4.2 ( 24.6 )
        Change at EoT: Constipation
    0.2 ( 21.8 )
    4.7 ( 25.1 )
        Change at FU Month 6: Constipation
    3.4 ( 23.2 )
    1.5 ( 24.1 )
        Change at FU Month 12: Constipation
    2.8 ( 22.8 )
    2.0 ( 23.3 )
        Change at FU Month 18: Constipation
    9999999 ( 9999999 )
    0.0 ( 0.0 )
        Baseline: Diarrhea
    5.2 ( 13.2 )
    4.7 ( 12.9 )
        Change at Cycle 1: Diarrhea
    4.7 ( 20.3 )
    4.2 ( 18.4 )
        Change at Cycle 2: Diarrhea
    32.5 ( 32.8 )
    16.0 ( 26.9 )
        Change at Cycle 3: Diarrhea
    28.4 ( 30.5 )
    11.3 ( 23.5 )
        Change at Cycle 4: Diarrhea
    26.5 ( 30.0 )
    10.3 ( 23.6 )
        Change at Cycle 5: Diarrhea
    23.9 ( 30.4 )
    8.8 ( 22.8 )
        Change at Cycle 9: Diarrhea
    12.6 ( 24.6 )
    4.7 ( 21.7 )
        Change at Cycle 14: Diarrhea
    12.5 ( 26.4 )
    5.1 ( 20.3 )
        Change at EoT: Diarrhea
    10.3 ( 25.2 )
    3.0 ( 19.4 )
        Change at FU Month 6: Diarrhea
    -0.3 ( 16.4 )
    -1.1 ( 16.3 )
        Change at FU Month 12: Diarrhea
    -0.3 ( 17.8 )
    0.0 ( 17.1 )
        Change at FU Month 18: Diarrhea
    9999999 ( 9999999 )
    -16.7 ( 23.6 )
        Baseline: Dyspnea
    5.8 ( 14.0 )
    6.2 ( 14.3 )
        Change at Cycle 1: Dyspnea
    10.4 ( 21.4 )
    9.2 ( 21.8 )
        Change at Cycle 2: Dyspnea
    11.6 ( 22.0 )
    7.4 ( 20.6 )
        Change at Cycle 3: Dyspnea
    13.4 ( 23.2 )
    6.5 ( 20.5 )
        Change at Cycle 4: Dyspnea
    14.3 ( 23.7 )
    5.9 ( 20.8 )
        Change at Cycle 5: Dyspnea
    13.7 ( 22.4 )
    5.6 ( 19.8 )
        Change at Cycle 9: Dyspnea
    7.8 ( 19.3 )
    7.5 ( 21.4 )
        Change at Cycle 14: Dyspnea
    6.8 ( 20.8 )
    8.1 ( 21.6 )
        Change at EoT: Dyspnea
    7.6 ( 21.1 )
    8.8 ( 22.3 )
        Change at FU Month 6: Dyspnea
    7.0 ( 20.8 )
    5.3 ( 19.7 )
        Change at FU Month 12: Dyspnea
    6.2 ( 20.9 )
    5.8 ( 20.5 )
        Change at FU Month 18: Dyspnea
    9999999 ( 9999999 )
    -16.7 ( 23.6 )
        Baseline: Fatigue
    21.5 ( 18.6 )
    20.6 ( 18.6 )
        Change at Cycle 1: Fatigue
    13.2 ( 21.5 )
    14.4 ( 22.1 )
        Change at Cycle 2: Fatigue
    15.4 ( 22.7 )
    11.2 ( 21.7 )
        Change at Cycle 3: Fatigue
    15.3 ( 23.1 )
    8.7 ( 20.9 )
        Change at Cycle 4: Fatigue
    16.0 ( 23.4 )
    8.2 ( 20.7 )
        Change at Cycle 5: Fatigue
    14.9 ( 22.8 )
    8.4 ( 21.1 )
        Change at Cycle 9: Fatigue
    8.4 ( 22.0 )
    9.8 ( 20.8 )
        Change at Cycle 14: Fatigue
    6.7 ( 22.0 )
    10.6 ( 22.4 )
        Change at EoT: Fatigue
    5.5 ( 22.9 )
    9.3 ( 21.9 )
        Change at FU Month 6: Fatigue
    2.8 ( 21.9 )
    3.1 ( 21.9 )
        Change at FU Month 12: Fatigue
    1.9 ( 22.1 )
    1.8 ( 20.8 )
        Change at FU Month 18: Fatigue
    9999999 ( 9999999 )
    -5.6 ( 39.3 )
        Baseline: Financial Difficulties
    20.1 ( 28.3 )
    19.9 ( 28.5 )
        Change at Cycle 1: Financial Difficulties
    2.2 ( 25.2 )
    0.3 ( 24.8 )
        Change at Cycle 2: Financial Difficulties
    2.0 ( 25.7 )
    -0.6 ( 25.3 )
        Change at Cycle 3: Financial Difficulties
    3.9 ( 24.7 )
    -0.4 ( 25.0 )
        Change at Cycle 4: Financial Difficulties
    3.7 ( 24.9 )
    -0.2 ( 25.4 )
        Change at Cycle 5: Financial Difficulties
    3.4 ( 25.3 )
    0.7 ( 26.2 )
        Change at Cycle 9: Financial Difficulties
    0.9 ( 25.6 )
    -0.5 ( 26.6 )
        Change at Cycle 14: Financial Difficulties
    -1.4 ( 25.1 )
    -1.0 ( 27.2 )
        Change at EoT: Financial Difficulties
    -1.1 ( 27.3 )
    -1.7 ( 25.7 )
        Change at FU Month 6: Financial Difficulties
    -3.8 ( 27.4 )
    -5.2 ( 28.7 )
        Change at FU Month 12: Financial Difficulties
    -5.1 ( 28.6 )
    -6.8 ( 28.3 )
        Change at FU Month 18: Financial Difficulties
    9999999 ( 9999999 )
    0.0 ( 0.0 )
        Baseline: Insomnia
    23.9 ( 26.1 )
    24.9 ( 27.6 )
        Change at Cycle 1: Insomnia
    3.6 ( 30.2 )
    1.8 ( 28.8 )
        Change at Cycle 2: Insomnia
    6.0 ( 30.5 )
    0.4 ( 30.0 )
        Change at Cycle 3: Insomnia
    6.2 ( 30.2 )
    -0.1 ( 30.3 )
        Change at Cycle 4: Insomnia
    8.6 ( 31.3 )
    1.1 ( 30.4 )
        Change at Cycle 5: Insomnia
    5.2 ( 31.1 )
    1.1 ( 29.9 )
        Change at Cycle 9: Insomnia
    4.3 ( 30.5 )
    1.1 ( 29.9 )
        Change at Cycle 14: Insomnia
    2.7 ( 30.6 )
    2.7 ( 30.2 )
        Change at EoT: Insomnia
    2.5 ( 30.8 )
    0.9 ( 30.2 )
        Change at FU Month 6: Insomnia
    0.9 ( 29.5 )
    -2.3 ( 29.6 )
        Change at FU Month 12: Insomnia
    0.0 ( 30.2 )
    -2.9 ( 30.4 )
        Change at FU Month 18: Insomnia
    9999999 ( 9999999 )
    -16.7 ( 23.6 )
        Baseline: Nausea/Vomiting
    2.6 ( 9.4 )
    2.3 ( 7.1 )
        Change at Cycle 1: Nausea/Vomiting
    10.4 ( 19.5 )
    10.5 ( 17.8 )
        Change at Cycle 2: Nausea/Vomiting
    6.0 ( 16.5 )
    7.5 ( 16.1 )
        Change at Cycle 3: Nausea/Vomiting
    5.0 ( 16.2 )
    5.2 ( 13.9 )
        Change at Cycle 4: Nausea/Vomiting
    4.7 ( 16.0 )
    3.7 ( 12.8 )
        Change at Cycle 5: Nausea/Vomiting
    4.0 ( 15.6 )
    3.2 ( 13.1 )
        Change at Cycle 9: Nausea/Vomiting
    1.1 ( 13.8 )
    2.8 ( 11.5 )
        Change at Cycle 14: Nausea/Vomiting
    1.1 ( 12.3 )
    3.0 ( 12.1 )
        Change at EoT: Nausea/Vomiting
    0.9 ( 13.2 )
    1.7 ( 12.0 )
        Change at FU Month 6: Nausea/Vomiting
    0.2 ( 11.6 )
    0.1 ( 10.1 )
        Change at FU Month 12: Nausea/Vomiting
    0.5 ( 12.4 )
    0.6 ( 10.3 )
        Change at FU Month 18: Nausea/Vomiting
    9999999 ( 9999999 )
    -8.3 ( 11.8 )
        Baseline: Pain
    17.4 ( 20.1 )
    16.4 ( 20.0 )
        Change at Cycle 1: Pain
    1.8 ( 22.8 )
    1.1 ( 22.5 )
        Change at Cycle 2: Pain
    5.0 ( 24.5 )
    2.8 ( 23.1 )
        Change at Cycle 3: Pain
    3.5 ( 23.7 )
    2.5 ( 22.6 )
        Change at Cycle 4: Pain
    5.4 ( 23.2 )
    3.1 ( 23.5 )
        Change at Cycle 5: Pain
    5.2 ( 23.7 )
    3.8 ( 23.5 )
        Change at Cycle 9: Pain
    3.4 ( 22.6 )
    3.9 ( 23.3 )
        Change at Cycle 14: Pain
    2.0 ( 23.4 )
    5.7 ( 24.1 )
        Change at EoT: Pain
    1.9 ( 23.3 )
    5.1 ( 24.5 )
        Change at FU Month 6: Pain
    0.8 ( 23.0 )
    1.4 ( 22.6 )
        Change at FU Month 12: Pain
    0.0 ( 23.3 )
    0.5 ( 21.5 )
        Change at FU Month 18: Pain
    9999999 ( 9999999 )
    -25.0 ( 35.4 )
        Baseline: Cognitive Functioning
    88.6 ( 16.9 )
    88.7 ( 16.3 )
        Change at Cycle 1: Cognitive Functioning
    -9.7 ( 20.8 )
    -6.9 ( 19.3 )
        Change at Cycle 2: Cognitive Functioning
    -9.4 ( 20.0 )
    -6.8 ( 19.3 )
        Change at Cycle 3: Cognitive Functioning
    -10.1 ( 20.8 )
    -6.4 ( 19.4 )
        Change at Cycle 4: Cognitive Functioning
    -11.8 ( 21.6 )
    -6.9 ( 19.6 )
        Change at Cycle 5: Cognitive Functioning
    -10.8 ( 21.6 )
    -7.3 ( 20.3 )
        Change at Cycle 9: Cognitive Functioning
    -8.3 ( 20.2 )
    -7.6 ( 20.1 )
        Change at Cycle 14: Cognitive Functioning
    -8.1 ( 20.3 )
    -8.1 ( 20.6 )
        Change at EoT: Cognitive Functioning
    -8.7 ( 22.3 )
    -8.4 ( 20.9 )
        Change at FU Month 6: Cognitive Functioning
    -8.0 ( 20.4 )
    -6.1 ( 19.7 )
        Change at FU Month 12: Cognitive Functioning
    -7.1 ( 22.5 )
    -6.0 ( 20.7 )
        Change at FU Month 18: Cognitive Functioning
    9999999 ( 9999999 )
    16.7 ( 23.6 )
        Baseline: Emotional Functioning
    76.0 ( 19.7 )
    75.7 ( 20.9 )
        Change at Cycle 1: Emotional Functioning
    -1.1 ( 20.3 )
    0.0 ( 19.2 )
        Change at Cycle 2: Emotional Functioning
    -1.0 ( 20.8 )
    1.6 ( 19.7 )
        Change at Cycle 3: Emotional Functioning
    -0.9 ( 21.2 )
    2.2 ( 19.6 )
        Change at Cycle 4: Emotional Functioning
    -2.5 ( 22.3 )
    2.8 ( 20.0 )
        Change at Cycle 5: Emotional Functioning
    -1.2 ( 22.2 )
    2.6 ( 21.1 )
        Change at Cycle 9: Emotional Functioning
    3.1 ( 20.9 )
    2.9 ( 21.1 )
        Change at Cycle 14: Emotional Functioning
    4.1 ( 21.0 )
    2.5 ( 21.3 )
        Change at EoT: Emotional Functioning
    3.0 ( 22.4 )
    3.1 ( 21.3 )
        Change at FU Month 6: Emotional Functioning
    4.7 ( 21.2 )
    6.1 ( 21.8 )
        Change at FU Month 12: Emotional Functioning
    5.8 ( 22.1 )
    6.5 ( 21.9 )
        Change at FU Month 18: Emotional Functioning
    9999999 ( 9999999 )
    12.5 ( 17.7 )
        Baseline: Physical Functioning
    88.4 ( 13.5 )
    89.1 ( 12.3 )
        Change at Cycle 1: Physical Functioning
    -6.0 ( 14.5 )
    -5.9 ( 13.4 )
        Change at Cycle 2: Physical Functioning
    -7.8 ( 15.8 )
    -4.8 ( 12.8 )
        Change at Cycle 3: Physical Functioning
    -7.1 ( 15.4 )
    -4.1 ( 13.0 )
        Change at Cycle 4: Physical Functioning
    -8.4 ( 16.2 )
    -3.5 ( 13.1 )
        Change at Cycle 5: Physical Functioning
    -8.3 ( 16.1 )
    -3.5 ( 13.3 )
        Change at Cycle 9: Physical Functioning
    -4.0 ( 15.0 )
    -3.8 ( 14.2 )
        Change at Cycle 14: Physical Functioning
    -2.7 ( 14.2 )
    -4.2 ( 14.2 )
        Change at EoT: Physical Functioning
    -2.2 ( 14.7 )
    -4.9 ( 15.0 )
        Change at FU Month 6: Physical Functioning
    -0.6 ( 14.4 )
    -1.6 ( 13.6 )
        Change at FU Month 12: Physical Functioning
    -0.1 ( 15.4 )
    -0.8 ( 13.2 )
        Change at FU Month 18: Physical Functioning
    9999999 ( 9999999 )
    13.3 ( 18.9 )
        Baseline: Role Functioning
    83.1 ( 21.7 )
    83.4 ( 21.3 )
        Change at Cycle 1: Role Functioning
    -5.1 ( 24.5 )
    -5.7 ( 24.9 )
        Change at Cycle 2: Role Functioning
    -9.7 ( 26.6 )
    -5.5 ( 24.0 )
        Change at Cycle 3: Role Functioning
    -8.9 ( 26.7 )
    -2.7 ( 23.2 )
        Change at Cycle 4: Role Functioning
    -10.7 ( 27.5 )
    -3.2 ( 23.7 )
        Change at Cycle 5: Role Functioning
    -9.4 ( 27.3 )
    -3.5 ( 23.9 )
        Change at Cycle 9: Role Functioning
    -3.3 ( 25.4 )
    -3.2 ( 24.1 )
        Change at Cycle 14: Role Functioning
    -0.5 ( 25.0 )
    -4.3 ( 25.3 )
        Change at EoT: Role Functioning
    -0.2 ( 26.3 )
    -3.5 ( 24.9 )
        Change at FU Month 6: Role Functioning
    2.2 ( 24.7 )
    2.4 ( 24.1 )
        Change at FU Month 12: Role Functioning
    2.6 ( 25.9 )
    3.7 ( 23.8 )
        Change at FU Month 18: Role Functioning
    9999999 ( 9999999 )
    8.3 ( 11.8 )
        Baseline: Social Functioning
    83.0 ( 22.9 )
    83.2 ( 21.6 )
        Change at Cycle 1: Social Functioning
    -8.0 ( 24.3 )
    -5.3 ( 22.8 )
        Change at Cycle 2: Social Functioning
    -10.1 ( 26.1 )
    -4.1 ( 23.6 )
        Change at Cycle 3: Social Functioning
    -9.5 ( 25.6 )
    -3.3 ( 24.4 )
        Change at Cycle 4: Social Functioning
    -10.3 ( 26.3 )
    -3.2 ( 24.2 )
        Change at Cycle 5: Social Functioning
    -8.7 ( 26.5 )
    -2.6 ( 23.7 )
        Change at Cycle 9: Social Functioning
    -1.7 ( 25.1 )
    -3.4 ( 24.9 )
        Change at Cycle 14: Social Functioning
    -0.1 ( 25.3 )
    -2.4 ( 24.9 )
        Change at EoT: Social Functioning
    0.3 ( 26.1 )
    -1.6 ( 24.1 )
        Change at FU Month 6: Social Functioning
    3.3 ( 24.8 )
    4.0 ( 24.7 )
        Change at FU Month 12: Social Functioning
    4.6 ( 25.2 )
    6.4 ( 22.7 )
        Change at FU Month 18: Social Functioning
    9999999 ( 9999999 )
    33.3 ( 47.1 )
        Baseline: Global Health Status
    74.3 ( 18.7 )
    73.9 ( 18.7 )
        Change at Cycle 1: Global Health Status
    -7.5 ( 20.1 )
    -7.2 ( 20.4 )
        Change at Cycle 2: Global Health Status
    -12.4 ( 22.6 )
    -7.1 ( 20.2 )
        Change at Cycle 3: Global Health Status
    -11.7 ( 20.6 )
    -5.2 ( 19.1 )
        Change at Cycle 4: Global Health Status
    -12.7 ( 21.3 )
    -5.5 ( 19.6 )
        Change at Cycle 5: Global Health Status
    -12.1 ( 21.7 )
    -5.8 ( 19.7 )
        Change at Cycle 9: Global Health Status
    -5.9 ( 20.1 )
    -6.4 ( 20.6 )
        Change at Cycle 14: Global Health Status
    -3.9 ( 21.1 )
    -6.3 ( 20.8 )
        Change at EoT: Global Health Status
    -3.5 ( 21.3 )
    -4.9 ( 20.7 )
        Change at FU Month 6: Global Health Status
    -0.6 ( 21.3 )
    0.3 ( 21.4 )
        Change at FU Month 12: Global Health Status
    -0.2 ( 21.9 )
    1.2 ( 20.8 )
        Change at FU Month 18: Global Health Status
    9999999 ( 9999999 )
    16.7 ( 23.6 )
    No statistical analyses for this end point

    Secondary: EORTC Quality of Life Questionnaire-Breast Cancer 23 (QLQ-BR23) Score

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    End point title
    		 EORTC Quality of Life Questionnaire-Breast Cancer 23 (QLQ-BR23) Score
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30. There are four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated improvement in quality of life (QOL) while negative change from baseline indicated a deterioration. For symptom scales, positive change from baseline indicated deterioration and negative change indicated improvement. The value '999999' indicates that the values were not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 1, 2, 3, 4, 5, 9, 14, End of Treatment, Follow-up Month 6, Follow-up Month 12, Follow-up Month 18
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    869
    891
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline: Arm Symptoms
    19.9 ( 18.7 )
    19.5 ( 18.4 )
        Change at Cycle 1: Arm Symptoms
    -1.3 ( 19.2 )
    -3.1 ( 18.7 )
        Change at Cycle 2: Arm Symptoms
    -2.8 ( 18.8 )
    -3.0 ( 18.7 )
        Change at Cycle 3: Arm Symptoms
    -3.5 ( 18.7 )
    -3.5 ( 18.1 )
        Change at Cycle 4: Arm Symptoms
    -2.0 ( 19.8 )
    -2.9 ( 19.2 )
        Change at Cycle 5: Arm Symptoms
    -0.5 ( 20.8 )
    -2.6 ( 19.8 )
        Change at Cycle 9: Arm Symptoms
    -0.2 ( 20.4 )
    -1.1 ( 19.6 )
        Change at Cycle 14: Arm Symptoms
    0.3 ( 21.3 )
    1.3 ( 21.8 )
        Change at EoT: Arm Symptoms
    0.1 ( 21.6 )
    0.4 ( 21.7 )
        Change at FU Month 6: Arm Symptoms
    -0.1 ( 22.1 )
    -1.3 ( 20.0 )
        Change at FU Month 12: Arm Symptoms
    -0.8 ( 22.4 )
    -2.8 ( 20.5 )
        Change at FU Month 18: Arm Symptoms
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Breast Symptoms
    17.5 ( 17.4 )
    16.8 ( 16.3 )
        Change at Cycle 1: Breast Symptoms
    -2.3 ( 16.3 )
    -2.5 ( 16.2 )
        Change at Cycle 2: Breast Symptoms
    -3.3 ( 17.1 )
    -2.9 ( 16.7 )
        Change at Cycle 3: Breast Symptoms
    -4.0 ( 17.5 )
    -3.1 ( 16.5 )
        Change at Cycle 4: Breast Symptoms
    -3.9 ( 17.7 )
    -3.3 ( 17.4 )
        Change at Cycle 5: Breast Symptoms
    -3.1 ( 18.6 )
    -2.6 ( 18.2 )
        Change at Cycle 9: Breast Symptoms
    1.7 ( 19.7 )
    0.3 ( 17.5 )
        Change at Cycle 14: Breast Symptoms
    -0.2 ( 18.8 )
    0.5 ( 19.1 )
        Change at EoT: Breast Symptoms
    -1.0 ( 19.3 )
    0.3 ( 18.8 )
        Change at FU Month 6: Breast Symptoms
    -2.5 ( 19.1 )
    -1.5 ( 18.4 )
        Change at FU Month 12: Breast Symptoms
    -4.2 ( 18.9 )
    -3.7 ( 18.0 )
        Change at FU Month 18: Breast Symptoms
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Systemic Therapy Side Effects (SE)
    8.5 ( 9.9 )
    8.7 ( 9.9 )
        Change at Cycle 1: Systemic Therapy SE
    24.9 ( 17.3 )
    23.3 ( 17.6 )
        Change at Cycle 2: Systemic Therapy SE
    24.1 ( 18.1 )
    18.3 ( 16.6 )
        Change at Cycle 3: Systemic Therapy SE
    23.4 ( 17.8 )
    15.1 ( 15.5 )
        Change at Cycle 4: Systemic Therapy SE
    23.1 ( 18.1 )
    13.2 ( 15.4 )
        Change at Cycle 5: Systemic Therapy SE
    20.0 ( 17.6 )
    11.8 ( 14.7 )
        Change at Cycle 9: Systemic Therapy SE
    9.5 ( 13.1 )
    10.4 ( 14.0 )
        Change at Cycle 14: Systemic Therapy SE
    7.5 ( 12.9 )
    9.8 ( 13.9 )
        Change at EoT: Systemic Therapy SE
    7.2 ( 13.4 )
    8.5 ( 13.9 )
        Change at FU Month 6: Systemic Therapy SE
    5.8 ( 12.3 )
    4.2 ( 12.5 )
        Change at FU Month 12: Systemic Therapy SE
    5.4 ( 12.9 )
    4.2 ( 13.0 )
        Change at FU Month 18: Systemic Therapy SE
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Upset by Hair Loss Item
    13.2 ( 23.7 )
    14.2 ( 22.9 )
        Change at Cycle 1: Upset by Hair Loss Item
    35.1 ( 37.3 )
    25.2 ( 35.1 )
        Change at Cycle 2: Upset by Hair Loss Item
    28.7 ( 36.0 )
    21.8 ( 36.6 )
        Change at Cycle 3: Upset by Hair Loss Item
    28.8 ( 36.3 )
    21.4 ( 38.4 )
        Change at Cycle 4: Upset by Hair Loss Item
    28.4 ( 37.1 )
    19.7 ( 34.2 )
        Change at Cycle 5: Upset by Hair Loss Item
    26.4 ( 36.8 )
    10.0 ( 36.3 )
        Change at Cycle 9: Upset by Hair Loss Item
    11.8 ( 33.6 )
    6.0 ( 36.8 )
        Change at Cycle 14: Upset by Hair Loss Item
    9.3 ( 32.5 )
    2.5 ( 26.0 )
        Change at EoT: Upset by Hair Loss Item
    17.3 ( 33.9 )
    0.0 ( 28.1 )
        Change at FU Month 6: Upset by Hair Loss Item
    6.2 ( 26.8 )
    -3.5 ( 21.0 )
        Change at FU Month 12: Upset by Hair Loss Item
    2.4 ( 28.7 )
    -2.8 ( 29.7 )
        Change at FU Month 18: Upset by Hair Loss Item
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Body Image
    78.5 ( 23.2 )
    78.9 ( 24.2 )
        Change at Cycle 1: Body Image
    -13.7 ( 23.5 )
    -13.3 ( 23.1 )
        Change at Cycle 2: Body Image
    -12.7 ( 23.9 )
    -10.1 ( 23.9 )
        Change at Cycle 3: Body Image
    -11.5 ( 24.8 )
    -6.6 ( 22.6 )
        Change at Cycle 4: Body Image
    -11.4 ( 24.8 )
    -5.9 ( 23.2 )
        Change at Cycle 5: Body Image
    -10.5 ( 24.6 )
    -5.0 ( 22.6 )
        Change at Cycle 9: Body Image
    -5.9 ( 22.8 )
    -4.2 ( 21.7 )
        Change at Cycle 14: Body Image
    -4.5 ( 23.6 )
    -2.4 ( 23.2 )
        Change at EoT: Body Image
    -3.3 ( 23.1 )
    -2.9 ( 22.8 )
        Change at FU Month 6: Body Image
    -1.3 ( 23.4 )
    0.3 ( 23.3 )
        Change at FU Month 12: Body Image
    0.0 ( 24.2 )
    0.7 ( 23.5 )
        Change at FU Month 18: Body Image
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Future Perspectives (FP)
    49.3 ( 31.4 )
    49.8 ( 30.9 )
        Change at Cycle 1: FP
    -1.3 ( 30.3 )
    -0.3 ( 31.1 )
        Change at Cycle 2: FP
    1.4 ( 31.7 )
    3.7 ( 30.4 )
        Change at Cycle 3: FP
    3.2 ( 32.0 )
    6.5 ( 30.1 )
        Change at Cycle 4: FP
    4.2 ( 31.7 )
    7.8 ( 30.5 )
        Change at Cycle 5: FP
    5.9 ( 32.4 )
    9.7 ( 30.7 )
        Change at Cycle 9: FP
    8.2 ( 32.2 )
    8.4 ( 31.3 )
        Change at Cycle 14: FP
    9.5 ( 32.0 )
    7.9 ( 33.4 )
        Change at EoT: FP
    8.5 ( 32.6 )
    7.6 ( 32.3 )
        Change at FU Month 6: FP
    10.5 ( 31.3 )
    12.6 ( 32.6 )
        Change at FU Month 12: FP
    15.0 ( 34.0 )
    13.1 ( 33.2 )
        Change at FU Month 18: FP
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Sexual Enjoyment
    43.4 ( 32.1 )
    46.7 ( 34.8 )
        Change at Cycle 1: Sexual Enjoyment
    -5.9 ( 26.8 )
    -8.2 ( 27.0 )
        Change at Cycle 2: Sexual Enjoyment
    -9.5 ( 30.2 )
    -10.7 ( 29.2 )
        Change at Cycle 3: Sexual Enjoyment
    -11.4 ( 26.8 )
    -8.9 ( 31.6 )
        Change at Cycle 4: Sexual Enjoyment
    -11.9 ( 30.6 )
    -9.2 ( 28.3 )
        Change at Cycle 5: Sexual Enjoyment
    -14.2 ( 28.1 )
    -8.8 ( 30.4 )
        Change at Cycle 9: Sexual Enjoyment
    -9.4 ( 29.5 )
    -7.4 ( 30.9 )
        Change at Cycle 14: Sexual Enjoyment
    -3.9 ( 28.6 )
    -9.7 ( 31.4 )
        Change at EoT: Sexual Enjoyment
    -6.5 ( 29.2 )
    -9.7 ( 29.4 )
        Change at FU Month 6: Sexual Enjoyment
    -4.6 ( 28.8 )
    -3.0 ( 30.5 )
        Change at FU Month 12: Sexual Enjoyment
    -5.7 ( 30.9 )
    -2.3 ( 31.0 )
        Change at FU Month 18: Sexual Enjoyment
    99999999 ( 9999999 )
    99999999 ( 9999999 )
        Baseline: Sexual Function
    16.7 ( 22.3 )
    18.3 ( 22.9 )
        Change at Cycle 1: Sexual Function
    -2.3 ( 18.9 )
    -3.5 ( 18.4 )
        Change at Cycle 2: Sexual Function
    -4.8 ( 19.9 )
    -4.4 ( 18.4 )
        Change at Cycle 3: Sexual Function
    -5.6 ( 19.6 )
    -3.3 ( 19.0 )
        Change at Cycle 4: Sexual Function
    -6.8 ( 19.7 )
    -3.4 ( 17.9 )
        Change at Cycle 5: Sexual Function
    -5.9 ( 19.5 )
    -3.0 ( 19.5 )
        Change at Cycle 9: Sexual Function
    -3.4 ( 19.3 )
    -1.8 ( 20.8 )
        Change at Cycle 14: Sexual Function
    -1.8 ( 20.0 )
    -2.8 ( 20.6 )
        Change at EoT: Sexual Function
    -1.5 ( 20.9 )
    -1.7 ( 19.7 )
        Change at FU Month 6: Sexual Function
    1.6 ( 22.6 )
    0.6 ( 20.4 )
        Change at FU Month 12: Sexual Function
    0.9 ( 21.7 )
    0.9 ( 20.9 )
        Change at FU Month 18: Sexual Function
    99999999 ( 9999999 )
    99999999 ( 9999999 )
    No statistical analyses for this end point

    Secondary: Time to Clinically Meaningful Deterioration in the Global Health Status/ Quality of Life and Functional (Physical, Role, and Cognitive) Subscales of the QLQ-C30 From First HER2-Targeted Treatment

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    End point title
    		 Time to Clinically Meaningful Deterioration in the Global Health Status/ Quality of Life and Functional (Physical, Role, and Cognitive) Subscales of the QLQ-C30 From First HER2-Targeted Treatment
    End point description
    The time to clinically meaningful deterioration in the global health status/Quality of life and Functional (Physical, Role, and Cognitive) subscales of the the QLQ-C30 was assessed from the time of the HER2-Targeted treatment to the worsening in the respective scales. Clinically meaningful deterioration is defined as a decrease in score of 10 points in Physical functioning and HRQoL; decrease of 7 points in Cognitive functioning, decrease of 14 points in Role functioning. The value '999999' indicates that the median and/or upper 95% CI were not reached.
    End point type
    Secondary
    End point timeframe
    From start of HER-2 targeted treatment up to 18 months after treatment discontinuation. The median time to clinically meaningful deterioration was assessed based on the data collection described above.
    End point values
    		 Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Number of subjects analysed
    864
    884
    Units: Months
    median (confidence interval 95%)
        GHS/QoL Score
    2.73 (2.10 to 2.83)
    13.57 (9.20 to 21.91)
        Physical Function
    25.53 (13.34 to 999999)
    999999 (27.43 to 999999)
        Role Function
    2.23 (2.10 to 2.79)
    9.92 (9.00 to 14.36)
        Cognitive Function
    5.49 (2.79 to 5.82)
    9.46 (8.57 to 12.91)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization to approximately 7.5 years
    Adverse event reporting additional description
    AEs were graded according to the NCI CTCAE Version 4.0. 8 participants were randomized but did not receive any study treatment (5 in the AC-THP arm, 3 in the AC-KP arm). 16 participants in the AC-THP, and 13 in the AC-KP arm only received AC but no HER2 targeted therapy and were consequently assigned to the AC-THP arm for safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
    Reporting group description
    		 Trastuzumab emtansine and pertuzumab continued for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.

    Reporting group title
    Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Reporting group description
    		 Trastuzumab and pertuzumab were administered concurrently for up to a total duration of 1 year (up to 18 cycles [1 Cycle = 21 days]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline [5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)] based chemotherapy.

    Serious adverse events
    		 Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Total subjects affected by serious adverse events
         subjects affected / exposed
    195 / 912 (21.38%)
    216 / 926 (23.33%)
         number of deaths (all causes)
    55
    45
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyosarcoma
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon neoplasm
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma of skin
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute promyelocytic leukaemia
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroma
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (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
    3 / 912 (0.33%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    19 / 912 (2.08%)
    13 / 926 (1.40%)
         occurrences causally related to treatment / all
    15 / 22
    8 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         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 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device pain
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site vesicles
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 912 (0.22%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    2 / 912 (0.22%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast necrosis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrocystic breast disease
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cyst
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 912 (0.00%)
    5 / 926 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus pain
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 912 (0.33%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 912 (0.33%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 912 (0.33%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 912 (0.00%)
    3 / 926 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    4 / 912 (0.44%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    9 / 912 (0.99%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    9 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation of wound
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation skin injury
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 912 (0.22%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 912 (0.22%)
    5 / 926 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 912 (0.11%)
    3 / 926 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 912 (0.11%)
    3 / 926 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 912 (0.22%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (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
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (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
    Thrombocytopenia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 912 (0.33%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    10 / 912 (1.10%)
    16 / 926 (1.73%)
         occurrences causally related to treatment / all
    11 / 11
    18 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    31 / 912 (3.40%)
    51 / 926 (5.51%)
         occurrences causally related to treatment / all
    32 / 32
    54 / 55
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Varices oesophageal
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 912 (0.77%)
    10 / 926 (1.08%)
         occurrences causally related to treatment / all
    4 / 7
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 912 (0.99%)
    6 / 926 (0.65%)
         occurrences causally related to treatment / all
    7 / 9
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 912 (0.88%)
    20 / 926 (2.16%)
         occurrences causally related to treatment / all
    4 / 8
    19 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 912 (0.44%)
    4 / 926 (0.43%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal hypertension
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular regenerative hyperplasia
         subjects affected / exposed
    3 / 912 (0.33%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 912 (0.22%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spider naevus
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 912 (0.44%)
    3 / 926 (0.32%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 912 (0.22%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 912 (0.00%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 912 (0.11%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 912 (0.11%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 912 (0.33%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    2 / 912 (0.22%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 912 (1.32%)
    12 / 926 (1.30%)
         occurrences causally related to treatment / all
    5 / 12
    5 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 912 (0.22%)
    3 / 926 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 912 (0.22%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    4 / 912 (0.44%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 912 (0.22%)
    3 / 926 (0.32%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 912 (0.22%)
    2 / 926 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    8 / 912 (0.88%)
    6 / 926 (0.65%)
         occurrences causally related to treatment / all
    4 / 8
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 912 (0.00%)
    8 / 926 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 912 (0.11%)
    4 / 926 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    1 / 912 (0.11%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 912 (0.11%)
    7 / 926 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 912 (0.00%)
    1 / 926 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 912 (0.22%)
    7 / 926 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 912 (0.11%)
    0 / 926 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    902 / 912 (98.90%)
    902 / 926 (97.41%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    100 / 912 (10.96%)
    167 / 926 (18.03%)
         occurrences all number
    110
    190
    Lymphoedema
         subjects affected / exposed
    30 / 912 (3.29%)
    68 / 926 (7.34%)
         occurrences all number
    31
    70
    Hypertension
         subjects affected / exposed
    63 / 912 (6.91%)
    36 / 926 (3.89%)
         occurrences all number
    83
    51
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    60 / 912 (6.58%)
    42 / 926 (4.54%)
         occurrences all number
    90
    58
    Mucosal inflammation
         subjects affected / exposed
    111 / 912 (12.17%)
    156 / 926 (16.85%)
         occurrences all number
    134
    213
    Asthenia
         subjects affected / exposed
    131 / 912 (14.36%)
    121 / 926 (13.07%)
         occurrences all number
    254
    222
    Pyrexia
         subjects affected / exposed
    227 / 912 (24.89%)
    175 / 926 (18.90%)
         occurrences all number
    353
    242
    Chills
         subjects affected / exposed
    67 / 912 (7.35%)
    40 / 926 (4.32%)
         occurrences all number
    79
    45
    Fatigue
         subjects affected / exposed
    419 / 912 (45.94%)
    439 / 926 (47.41%)
         occurrences all number
    659
    672
    Influenza like illness
         subjects affected / exposed
    62 / 912 (6.80%)
    26 / 926 (2.81%)
         occurrences all number
    72
    33
    Oedema peripheral
         subjects affected / exposed
    74 / 912 (8.11%)
    156 / 926 (16.85%)
         occurrences all number
    91
    173
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    55 / 912 (6.03%)
    45 / 926 (4.86%)
         occurrences all number
    65
    57
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    333 / 912 (36.51%)
    182 / 926 (19.65%)
         occurrences all number
    487
    226
    Dyspnoea
         subjects affected / exposed
    79 / 912 (8.66%)
    73 / 926 (7.88%)
         occurrences all number
    91
    87
    Oropharyngeal pain
         subjects affected / exposed
    100 / 912 (10.96%)
    111 / 926 (11.99%)
         occurrences all number
    123
    132
    Rhinorrhoea
         subjects affected / exposed
    82 / 912 (8.99%)
    77 / 926 (8.32%)
         occurrences all number
    96
    87
    Cough
         subjects affected / exposed
    157 / 912 (17.21%)
    148 / 926 (15.98%)
         occurrences all number
    190
    189
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    155 / 912 (17.00%)
    171 / 926 (18.47%)
         occurrences all number
    190
    204
    Depression
         subjects affected / exposed
    52 / 912 (5.70%)
    52 / 926 (5.62%)
         occurrences all number
    54
    54
    Anxiety
         subjects affected / exposed
    42 / 912 (4.61%)
    58 / 926 (6.26%)
         occurrences all number
    48
    63
    Investigations
    Weight decreased
         subjects affected / exposed
    79 / 912 (8.66%)
    57 / 926 (6.16%)
         occurrences all number
    82
    61
    Neutrophil count decreased
         subjects affected / exposed
    75 / 912 (8.22%)
    83 / 926 (8.96%)
         occurrences all number
    135
    148
    Blood bilirubin increased
         subjects affected / exposed
    80 / 912 (8.77%)
    4 / 926 (0.43%)
         occurrences all number
    127
    6
    Ejection fraction decreased
         subjects affected / exposed
    29 / 912 (3.18%)
    61 / 926 (6.59%)
         occurrences all number
    35
    72
    Alanine aminotransferase increased
         subjects affected / exposed
    301 / 912 (33.00%)
    108 / 926 (11.66%)
         occurrences all number
    418
    134
    Aspartate aminotransferase increased
         subjects affected / exposed
    317 / 912 (34.76%)
    98 / 926 (10.58%)
         occurrences all number
    431
    113
    Platelet count decreased
         subjects affected / exposed
    143 / 912 (15.68%)
    15 / 926 (1.62%)
         occurrences all number
    203
    21
    Blood alkaline phosphatase increased
         subjects affected / exposed
    85 / 912 (9.32%)
    20 / 926 (2.16%)
         occurrences all number
    100
    24
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    205 / 912 (22.48%)
    207 / 926 (22.35%)
         occurrences all number
    213
    210
    Infusion related reaction
         subjects affected / exposed
    126 / 912 (13.82%)
    115 / 926 (12.42%)
         occurrences all number
    157
    132
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    101 / 912 (11.07%)
    85 / 926 (9.18%)
         occurrences all number
    129
    102
    Dysgeusia
         subjects affected / exposed
    162 / 912 (17.76%)
    180 / 926 (19.44%)
         occurrences all number
    177
    205
    Headache
         subjects affected / exposed
    261 / 912 (28.62%)
    234 / 926 (25.27%)
         occurrences all number
    419
    328
    Dizziness
         subjects affected / exposed
    105 / 912 (11.51%)
    117 / 926 (12.63%)
         occurrences all number
    138
    140
    Neuropathy peripheral
         subjects affected / exposed
    140 / 912 (15.35%)
    163 / 926 (17.60%)
         occurrences all number
    164
    204
    Peripheral sensory neuropathy
         subjects affected / exposed
    193 / 912 (21.16%)
    214 / 926 (23.11%)
         occurrences all number
    209
    236
    Taste disorder
         subjects affected / exposed
    60 / 912 (6.58%)
    56 / 926 (6.05%)
         occurrences all number
    69
    67
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    220 / 912 (24.12%)
    232 / 926 (25.05%)
         occurrences all number
    403
    411
    Leukopenia
         subjects affected / exposed
    51 / 912 (5.59%)
    73 / 926 (7.88%)
         occurrences all number
    96
    134
    Anaemia
         subjects affected / exposed
    174 / 912 (19.08%)
    184 / 926 (19.87%)
         occurrences all number
    243
    249
    Thrombocytopenia
         subjects affected / exposed
    162 / 912 (17.76%)
    25 / 926 (2.70%)
         occurrences all number
    297
    29
    Eye disorders
    Vision blurred
         subjects affected / exposed
    46 / 912 (5.04%)
    42 / 926 (4.54%)
         occurrences all number
    49
    44
    Dry eye
         subjects affected / exposed
    75 / 912 (8.22%)
    62 / 926 (6.70%)
         occurrences all number
    87
    69
    Lacrimation increased
         subjects affected / exposed
    73 / 912 (8.00%)
    112 / 926 (12.10%)
         occurrences all number
    75
    120
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    228 / 912 (25.00%)
    276 / 926 (29.81%)
         occurrences all number
    338
    441
    Dry mouth
         subjects affected / exposed
    105 / 912 (11.51%)
    63 / 926 (6.80%)
         occurrences all number
    116
    68
    Gingival bleeding
         subjects affected / exposed
    57 / 912 (6.25%)
    6 / 926 (0.65%)
         occurrences all number
    64
    6
    Dyspepsia
         subjects affected / exposed
    106 / 912 (11.62%)
    123 / 926 (13.28%)
         occurrences all number
    123
    146
    Vomiting
         subjects affected / exposed
    289 / 912 (31.69%)
    243 / 926 (26.24%)
         occurrences all number
    502
    358
    Abdominal pain upper
         subjects affected / exposed
    87 / 912 (9.54%)
    83 / 926 (8.96%)
         occurrences all number
    110
    90
    Constipation
         subjects affected / exposed
    299 / 912 (32.79%)
    287 / 926 (30.99%)
         occurrences all number
    413
    369
    Nausea
         subjects affected / exposed
    605 / 912 (66.34%)
    596 / 926 (64.36%)
         occurrences all number
    1246
    1034
    Diarrhoea
         subjects affected / exposed
    405 / 912 (44.41%)
    605 / 926 (65.33%)
         occurrences all number
    759
    1158
    Haemorrhoids
         subjects affected / exposed
    46 / 912 (5.04%)
    58 / 926 (6.26%)
         occurrences all number
    50
    71
    Abdominal pain
         subjects affected / exposed
    86 / 912 (9.43%)
    83 / 926 (8.96%)
         occurrences all number
    110
    103
    Gastrooesophageal reflux disease
         subjects affected / exposed
    39 / 912 (4.28%)
    58 / 926 (6.26%)
         occurrences all number
    41
    64
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    598 / 912 (65.57%)
    629 / 926 (67.93%)
         occurrences all number
    616
    651
    Rash
         subjects affected / exposed
    214 / 912 (23.46%)
    249 / 926 (26.89%)
         occurrences all number
    290
    353
    Dermatitis acneiform
         subjects affected / exposed
    53 / 912 (5.81%)
    52 / 926 (5.62%)
         occurrences all number
    60
    59
    Nail discolouration
         subjects affected / exposed
    76 / 912 (8.33%)
    104 / 926 (11.23%)
         occurrences all number
    78
    104
    Nail disorder
         subjects affected / exposed
    43 / 912 (4.71%)
    68 / 926 (7.34%)
         occurrences all number
    43
    72
    Rash maculo-papular
         subjects affected / exposed
    42 / 912 (4.61%)
    47 / 926 (5.08%)
         occurrences all number
    59
    56
    Erythema
         subjects affected / exposed
    75 / 912 (8.22%)
    86 / 926 (9.29%)
         occurrences all number
    82
    100
    Dry skin
         subjects affected / exposed
    100 / 912 (10.96%)
    132 / 926 (14.25%)
         occurrences all number
    112
    143
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    25 / 912 (2.74%)
    66 / 926 (7.13%)
         occurrences all number
    31
    74
    Pruritus
         subjects affected / exposed
    126 / 912 (13.82%)
    169 / 926 (18.25%)
         occurrences all number
    151
    222
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    93 / 912 (10.20%)
    120 / 926 (12.96%)
         occurrences all number
    111
    138
    Pain in extremity
         subjects affected / exposed
    114 / 912 (12.50%)
    119 / 926 (12.85%)
         occurrences all number
    136
    154
    Arthralgia
         subjects affected / exposed
    261 / 912 (28.62%)
    289 / 926 (31.21%)
         occurrences all number
    338
    397
    Muscle spasms
         subjects affected / exposed
    97 / 912 (10.64%)
    86 / 926 (9.29%)
         occurrences all number
    129
    92
    Bone pain
         subjects affected / exposed
    58 / 912 (6.36%)
    70 / 926 (7.56%)
         occurrences all number
    71
    94
    Myalgia
         subjects affected / exposed
    152 / 912 (16.67%)
    214 / 926 (23.11%)
         occurrences all number
    195
    255
    Infections and infestations
    Paronychia
         subjects affected / exposed
    50 / 912 (5.48%)
    53 / 926 (5.72%)
         occurrences all number
    54
    59
    Urinary tract infection
         subjects affected / exposed
    63 / 912 (6.91%)
    73 / 926 (7.88%)
         occurrences all number
    82
    99
    Upper respiratory tract infection
         subjects affected / exposed
    125 / 912 (13.71%)
    139 / 926 (15.01%)
         occurrences all number
    176
    197
    Nasopharyngitis
         subjects affected / exposed
    171 / 912 (18.75%)
    175 / 926 (18.90%)
         occurrences all number
    257
    269
    Conjunctivitis
         subjects affected / exposed
    42 / 912 (4.61%)
    49 / 926 (5.29%)
         occurrences all number
    44
    51
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    67 / 912 (7.35%)
    41 / 926 (4.43%)
         occurrences all number
    102
    50
    Decreased appetite
         subjects affected / exposed
    244 / 912 (26.75%)
    241 / 926 (26.03%)
         occurrences all number
    371
    348

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2014
    Safety data reports related to concurrent radiotherapy and/or hormonal therapy will be monitored by the iDMC at least once every 3 months; HCV RNA testing was added to the exclusion criteria; Criteria for dose recalculation due to weight change was updated; Pulmonary Toxicity was updated to remove language regarding advanced malignancy; Hepatotoxicity was updated to provide clarity on Hy's law and to match the latest Trastuzumab Emtansine Investigator’s Brochure; Anthracycline Treatment Phase and Trastuzumab plus Pertuzumab plus Taxane Treatment Arm−1 sections were updated to provide the guidance to refer to local prescribing information for contraindications, requirements on contraception duration, and concomitant medications; Dose Modifications and Delays were updated; Additional information added regarding sample size calculation for the invasive disease−free survival (IDFS) primary endpoint.
    30 Jul 2015
    Sample size was reduced while maintaining statistical validity of the study in addressing its primary endpoint; the Rationale for Adjuvant Regimens and Duration of Therapy was updated to reflect the impact of new data.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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