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    Clinical Trial Results:
    A Randomized Multicenter, Double-Blind, Placebo-Controlled Comparison of Chemotherapy Plus Trastuzumab Plus Placebo Versus Chemotherapy Plus Trastuzumab Plus Pertuzumab as Adjuvant Therapy in Patients with Operable HER2-Positive Primary Breast Cancer

    Summary
    EudraCT number
    2010-022902-41
    Trial protocol
    GB   HU   CZ   ES   FR   IE   SE   DK   SI   NL   BE   SK   AT   IT   BG  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Dec 2017
    First version publication date
    22 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO25126
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01358877
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Genentech protocol code: TOC4939g, Breast International Group: BIG 4-11
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    Interim
    Date of interim/final analysis
    19 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare invasive disease-free survival (IDFS) (excluding second non breast cancers) in participants with human epidermal growth receptor 2 (HER2)-positive early breast cancer randomized to chemotherapy plus 1 year of trastuzumab plus placebo, or chemotherapy plus 1 year of trastuzumab plus pertuzumab.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol. Approval from the Institutional Review Board (IRB)/Ethics Committees (ECs) was obtained before study start. The sponsor also obtained approval from the relevant regulatory authorities prior to starting the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 109
    Country: Number of subjects enrolled
    Austria: 52
    Country: Number of subjects enrolled
    Belgium: 131
    Country: Number of subjects enrolled
    Bulgaria: 21
    Country: Number of subjects enrolled
    Canada: 110
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    China: 372
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Croatia: 15
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    Denmark: 87
    Country: Number of subjects enrolled
    El Salvador: 7
    Country: Number of subjects enrolled
    France: 544
    Country: Number of subjects enrolled
    Germany: 460
    Country: Number of subjects enrolled
    Guatemala: 12
    Country: Number of subjects enrolled
    Hong Kong: 16
    Country: Number of subjects enrolled
    Hungary: 63
    Country: Number of subjects enrolled
    Ireland: 43
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    Italy: 255
    Country: Number of subjects enrolled
    Japan: 302
    Country: Number of subjects enrolled
    Mexico: 35
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    New Zealand: 19
    Country: Number of subjects enrolled
    Panama: 15
    Country: Number of subjects enrolled
    Peru: 25
    Country: Number of subjects enrolled
    Philippines: 36
    Country: Number of subjects enrolled
    Poland: 110
    Country: Number of subjects enrolled
    Romania: 25
    Country: Number of subjects enrolled
    Russian Federation: 58
    Country: Number of subjects enrolled
    Slovenia: 9
    Country: Number of subjects enrolled
    South Africa: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 136
    Country: Number of subjects enrolled
    Spain: 343
    Country: Number of subjects enrolled
    Sweden: 72
    Country: Number of subjects enrolled
    Switzerland: 50
    Country: Number of subjects enrolled
    Taiwan: 170
    Country: Number of subjects enrolled
    Thailand: 75
    Country: Number of subjects enrolled
    Ukraine: 73
    Country: Number of subjects enrolled
    United Kingdom: 224
    Country: Number of subjects enrolled
    United States: 590
    Worldwide total number of subjects
    4804
    EEA total number of subjects
    2504
    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)
    4196
    From 65 to 84 years
    605
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The analysis included data up to a clinical data cut-off date of 19 December 2016.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pertuzumab + Trastuzumab + Chemotherapy
    Arm description
    Participants received pertuzumab (840 mg loading dose, then 420 mg) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) intravenously (IV) every 3 weeks (Q3W) for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 once weekly (QW); 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin area under the curve (AUC) 6 (up to 900 mg).
    Arm type
    Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    RO4368451
    Other name
    Perjeta®, rhuMAb 2C4
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab will be administered as per the schedule specified in the arm description.

    Arm title
    Placebo + Trastuzumab + Chemotherapy
    Arm description
    Participants received placebo matched to pertuzumab IV Q3W and trastuzumab (8 milligrams per kilogram [mg/kg] loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 milligrams per square meter (mg/m^2) + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 milligrams [mg]).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to pertuzumab will be administered as per the schedule specified in the arm.

    Number of subjects in period 1
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Started
    2400
    2404
    Completed
    0
    0
    Not completed
    2400
    2404
         Ongoing follow-up for overall survival
    7
    5
         Ongoing follow-up for IDFS event
    2084
    2073
         Death
    80
    89
         Ongoing follow-up for post-recurrence
    87
    108
         Unspecified
    142
    129

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Chemotherapy
    Reporting group description
    Participants received pertuzumab (840 mg loading dose, then 420 mg) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) intravenously (IV) every 3 weeks (Q3W) for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 once weekly (QW); 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin area under the curve (AUC) 6 (up to 900 mg).

    Reporting group title
    Placebo + Trastuzumab + Chemotherapy
    Reporting group description
    Participants received placebo matched to pertuzumab IV Q3W and trastuzumab (8 milligrams per kilogram [mg/kg] loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 milligrams per square meter (mg/m^2) + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 milligrams [mg]).

    Reporting group values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy Total
    Number of subjects
    2400 2404 4804
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.7 ( 10.9 ) 51.4 ( 10.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    2397 2396 4793
        Male
    3 8 11

    End points

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    End points reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Chemotherapy
    Reporting group description
    Participants received pertuzumab (840 mg loading dose, then 420 mg) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) intravenously (IV) every 3 weeks (Q3W) for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 once weekly (QW); 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin area under the curve (AUC) 6 (up to 900 mg).

    Reporting group title
    Placebo + Trastuzumab + Chemotherapy
    Reporting group description
    Participants received placebo matched to pertuzumab IV Q3W and trastuzumab (8 milligrams per kilogram [mg/kg] loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 milligrams per square meter (mg/m^2) + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 milligrams [mg]).

    Subject analysis set title
    Pertuzumab + Trastuzumab + Chemotherapy
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received pertuzumab (840 mg loading dose, then 420 mg) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 mg).

    Subject analysis set title
    Placebo + Trastuzumab + Chemotherapy
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received placebo matched to pertuzumab IV Q3W and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 mg).

    Subject analysis set title
    Pertuzumab + Trastuzumab + Chemotherapy
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received pertuzumab (840 mg loading dose, then 420 mg) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 mg).

    Subject analysis set title
    Placebo + Trastuzumab + Chemotherapy
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received placebo matched to pertuzumab IV Q3W and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 mg).

    Primary: Percentage of Participants With IDFS Event (Excluding Second Primary Non-Breast Cancer [SPNBC]), as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Percentage of Participants With IDFS Event (Excluding Second Primary Non-Breast Cancer [SPNBC]), as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Percentage of participants with IDFS events (excluding SPNBC) is reported. IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (that is [i.e.], an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. All SPNBCs and in situ carcinomas (including ductal carcinoma in situ [DCIS] and lobular carcinoma in situ [LCIS]) and non-melanoma skin cancer were excluded as an event. Intent-to-treat (ITT) population included all randomized participants regardless of treatment received.
    End point type
    Primary
    End point timeframe
    Randomization to the first occurrence of IDFS event (excluding SPNBC) (until data cut-off date 19 December 2016, up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
        number (not applicable)
    7.1
    8.7
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using stratified log-rank test, which included nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen as stratification factors in the randomization. Hazard ratios were estimated by Cox regression.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4804
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0446 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1
    Notes
    [1] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Primary: Kaplan-Meier Estimate of the Percentage of Participants Who Were IDFS Event-Free (Excluding SPNBC) at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Kaplan-Meier Estimate of the Percentage of Participants Who Were IDFS Event-Free (Excluding SPNBC) at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings [2]
    End point description
    Kaplan-Meier estimate of the percentage of participants who were IDFS event-free (excluding SPNBC) at Year 3 is reported. IDFS event the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. All SPNBCs and in situ carcinomas (including DCIS and LCIS) and non-melanoma skin cancer were excluded as an event. ITT population. Number of subjects analysed = participants remaining at risk for IDFS event (excluding SPNBC) at Year 3.
    End point type
    Primary
    End point timeframe
    3 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary outcome measure was analyzed for a relative treatment difference using the hazard ratio and log-rank test. Kaplan-Meier 3-year estimates of the primary outcome measure are only presented as additional descriptive summary statistics.
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2101
    2108
    Units: estimate of percentage of participants
        number (confidence interval 95%)
    94.06 (93.09 to 95.03)
    93.24 (92.21 to 94.26)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With IDFS Event (Including SPNBC), as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Percentage of Participants With IDFS Event (Including SPNBC), as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Percentage of participants with IDFS events (including SPNBC) is reported. IDFS-SPNBC event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer; SPNBC (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). ITT population.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of IDFS event (including SPNBC) (until data cut-off date 19 December 2016, up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
        number (not applicable)
    7.9
    9.6
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using stratified log-rank test, which included nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen as stratification factors in the randomization. Hazard ratios were estimated by Cox regression.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4804
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.043 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    0.99
    Notes
    [3] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Were IDFS Event-Free (Including SPNBC) at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Kaplan-Meier Estimate of the Percentage of Participants Who Were IDFS Event-Free (Including SPNBC) at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Kaplan-Meier estimate of the percentage of participants who were IDFS event-free (including SPNBC) at Year 3 is reported. IDFS-SPNBC event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer; SPNBC (with the exception of non-melanoma skin cancers and in situ carcinoma of any site). ITT population. Number of subjects analysed = participants remaining at risk for IDFS event (including SPNBC) at Year 3.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2093
    2095
    Units: estimate of percentage of participants
        number (confidence interval 95%)
    93.50 (92.49 to 94.51)
    92.51 (91.43 to 93.58)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease-Free Survival (DFS) Event, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Percentage of Participants With Disease-Free Survival (DFS) Event, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Percentage of participants with DFS event is reported. DFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer; SPNBC or contralateral or ipsilateral DCIS. ITT population.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of DFS event (until data cut-off date 19 December 2016, up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
        number (not applicable)
    8.0
    9.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using stratified log-rank test, which included nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen as stratification factors in the randomization. Hazard ratios were estimated by Cox regression.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4804
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0327 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    0.98
    Notes
    [4] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Were DFS Event-Free at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Kaplan-Meier Estimate of the Percentage of Participants Who Were DFS Event-Free at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Kaplan-Meier estimate of the percentage of participants who were DFS event-free at Year 3 is reported. DFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer; SPNBC or contralateral or ipsilateral DCIS. ITT population. Number of subjects analysed = participants remaining at risk for DFS event at Year 3.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2091
    2090
    Units: estimate of percentage of participants
        number (confidence interval 95%)
    93.42 (92.40 to 94.43)
    92.29 (91.21 to 93.38)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    Percentage of Participants Who Died
    End point description
    Percentage of participants who died due to any cause is reported. ITT population.
    End point type
    Secondary
    End point timeframe
    Randomization until death due to any cause (until data cut-off date 19 December 2016, up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
        number (not applicable)
    3.3
    3.7
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using stratified log-rank test, which included nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen as stratification factors in the randomization. Hazard ratios were estimated by Cox regression.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4804
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4673 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.21
    Notes
    [5] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Were Alive at Year 3

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    End point title
    Kaplan-Meier Estimate of the Percentage of Participants Who Were Alive at Year 3
    End point description
    The Kaplan-Meier approach was used to estimate the percentage of participants who were alive at 3 years. ITT population. Number of subjects analysed = participants remaining at risk for death at Year 3.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2186
    2209
    Units: estimate of percentage of participants
        number (confidence interval 95%)
    97.65 (97.03 to 98.27)
    97.67 (97.06 to 98.29)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Recurrence-Free Interval (RFI) Event, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Percentage of Participants With Recurrence-Free Interval (RFI) Event, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Percentage of participants with RFI event is reported. RFI event was defined as local, regional or distant breast cancer recurrence. ITT population.
    End point type
    Secondary
    End point timeframe
    Randomization until local, regional or distant breast cancer recurrence (until data cut-off date 19 December 2016, up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
        number (not applicable)
    5.8
    7.2
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using stratified log-rank test, which included nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen as stratification factors in the randomization. Hazard ratio were estimated by Cox regression.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4804
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.043
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    0.99

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Were RFI Event-Free at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Kaplan-Meier Estimate of the Percentage of Participants Who Were RFI Event-Free at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Kaplan-Meier estimate of the percentage of participants who were RFI event-free at Year 3 is reported. RFI event was defined local, regional or distant breast cancer recurrence. ITT population. Number of subjects analysed = participants remaining at risk for RFI event at Year 3.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2116
    2129
    Units: estimate of percentage of participants
        number (confidence interval 95%)
    95.18 (94.30 to 96.06)
    94.27 (93.32 to 95.21)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Distant Recurrence-Free Interval (DRFI) Event, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Percentage of Participants With Distant Recurrence-Free Interval (DRFI) Event, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Percentage of participants with DRFI event is reported. DRFI event was defined as distant breast cancer recurrence. ITT population.
    End point type
    Secondary
    End point timeframe
    Randomization until distant breast cancer recurrence (until data cut-off date 19 December 2016, up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
        number (not applicable)
    5.0
    6.0
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using stratified log-rank test, which included nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen as stratification factors in the randomization. Hazard ratio were estimated by Cox regression.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4804
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1007
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.04

    Secondary: Kaplan-Meier Estimate of the Percentage of Participants Who Were DRFI Event-Free at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings

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    End point title
    Kaplan-Meier Estimate of the Percentage of Participants Who Were DRFI Event-Free at Year 3, as Assessed Using Radiologic, Histologic Examinations or Laboratory Findings
    End point description
    Kaplan-Meier estimate of the percentage of participants who were DRFI event-free at Year 3 is reported. DRFI event was defined as distant breast cancer recurrence. ITT population. Number of subjects analysed = participants remaining at risk for DRFI event at Year 3.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2126
    2145
    Units: estimate of percentage of participants
        number (confidence interval 95%)
    95.70 (94.86 to 96.53)
    95.13 (94.25 to 96.00)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Primary Cardiac Event

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    End point title
    Percentage of Participants With Primary Cardiac Event
    End point description
    Primary cardiac event was defined as either: Heart Failure (New York Heart Association [NYHA] Class III or IV) and a drop in left ventricular ejection fraction (LVEF) of at least 10 ejection fraction (EF) points from baseline and to below 50 percent (%); or cardiac death. Cardiac death was defined as either definite cardiac death: due to heart failure, myocardial infarction, or documented primary arrhythmia; or probable cardiac death: sudden unexpected death within 24 hours of a definite or probable cardiac event (e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia) without documented etiology. Safety population included participants who received any amount of study medication (chemotherapy, pertuzumab/placebo, or trastuzumab), according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Baseline until data cut-off date 19 December 2016 (up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2364
    2405
    Units: percentage of participants
    number (not applicable)
        Primary Cardiac Event (Composite)
    0.7
    0.3
        Heart Failure and LVEF decline
    0.6
    0.2
        Cardiac Death (Definite or Probable)
    0.1
    0.1
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The difference in percentage of participants with a primary cardiac event between the pertuzumab and placebo arms. The 95% confidence interval (CI) was estimated using Hauck-Anderson correction.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4769
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment Difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.8

    Secondary: Percentage of Participants With Secondary Cardiac Event

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    End point title
    Percentage of Participants With Secondary Cardiac Event
    End point description
    Secondary cardiac event was defined as asymptomatic or mildly symptomatic (NYHA Class II) significant drop in LVEF (defined as an absolute decrease of at least 10 EF points from baseline and to below 50%), confirmed by a second LVEF assessment within approximately three weeks of the first significant LVEF assessment or confirmed by the Cardiac Advisory Board (CAB). Safety population.
    End point type
    Secondary
    End point timeframe
    Baseline until data cut-off date 19 December 2016 (up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2364
    2405
    Units: percentage of participants
        number (not applicable)
    2.7
    2.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    95% CI was estimated using Hauck-Anderson correction.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4769
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.9

    Secondary: Change From Baseline in LVEF to Worst Post-Baseline Value

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    End point title
    Change From Baseline in LVEF to Worst Post-Baseline Value
    End point description
    LVEF is the fraction of blood (in percent) pumped out of the heart’s left ventricular chamber with each heart beat, and is a measure of cardiac output for the heart. Baseline LVEF value and the maximum absolute decrease (worst value) in LVEF measurement from baseline were reported. LVEF was measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan. Safety population. "Number of subjects analysed"=participants evaluable for this endpoint. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline until data cut-off date 19 December 2016 (up to maximum length of follow-up of 59 months)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2363
    2401
    Units: percentage of blood pumped out
    arithmetic mean (standard deviation)
        Baseline (n=2363, 2401)
    65.2 ( 5.9 )
    65.3 ( 6.1 )
        Change to Worst Value (n=2348, 2351)
    -7.5 ( 6.6 )
    -7.6 ( 6.7 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    95% CI was estimated using Hauck-Anderson correction.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    4764
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.5

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score

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    End point title
    Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) Global Health Status (GHS) Scale Score
    End point description
    EORTC QLQ-C30 is a cancer-specific instrument with 30 questions used to assess overall quality of life(QOL)in cancer participants. First 28 questions used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much)for evaluating 5 functional scales(physical, role, social, cognitive, emotional),8 symptom scales(diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea and vomiting[N/V], constipation, pain) and a single item (financial difficulties). Last 2 questions represented participant’s assessment of overall health and quality of life, used 7-point scale(1=very poor to 7=excellent). Global scores were linearly transformed on a scale of 0 to 100, with a high score indicating better GHS/QOL. Negative change from Baseline values indicated deterioration in QOL or functioning. ITT population. "Number of subjects analysed"=participants evaluable for this endpoint. n= participants responding to this scale where it is considered complete as defined by EORTC QLQ-C30 scoring manual.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; end of treatment (EOT, 28 days after the last dose, up to Week 56); Follow-up (FU) Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2329
    2338
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2329, 2338)
    72.9 ( 19.7 )
    72.5 ( 19.7 )
        Change at Week 13 (n=2065, 2110)
    -11.2 ( 22.8 )
    -10.2 ( 22.6 )
        Change at Week 25 (n=2035, 2073)
    -4.4 ( 21.6 )
    -2.9 ( 21.0 )
        Change at EOT (n=2254, 2282)
    -3.1 ( 21.9 )
    -1.1 ( 21.8 )
        Change at FU Month 18 (n=1906, 1918)
    1.9 ( 21.5 )
    1.3 ( 22.2 )
        Change at FU Month 24 (n=1861, 1866)
    2.2 ( 22.1 )
    2.4 ( 22.1 )
        Change at FU Month 36 (n=1811, 1782)
    2.8 ( 21.4 )
    1.8 ( 22.5 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EORTC QLQ-C30 Functioning Subscale Scores

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    End point title
    Change From Baseline in EORTC QLQ-C30 Functioning Subscale Scores
    End point description
    EORTC QLQ-C30 is a cancer-specific instrument with 30 questions used to assess overall QOL in cancer participants. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, social, cognitive, emotional), 8 symptom scales (diarrhea, fatigue, dyspnea, appetite loss, insomnia, N/V, constipation, and pain) and a single item (financial difficulties). Last 2 questions represented participant’s assessment of overall health and quality of life, coded on 7-point scale(1=very poor to 7=excellent). EORTC QLQ-C30 functioning scores were linearly transformed on a scale of 0 to 100, with a high score indicating better functioning/support. Negative change from Baseline values indicated deterioration in functioning. ITT population. "Number of subjects analysed"=participants evaluable for this endpoint. n= participants responding to this scale where it is considered complete as defined by EORTC QLQ-C30 scoring manual.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2338
    2342
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2338, 2342): Physical
    89.6 ( 12.9 )
    89.1 ( 13.4 )
        Change at Week 13 (n=2077, 2115): Physical
    -10.7 ( 17.2 )
    -10.6 ( 17.7 )
        Change at Week 25 (n=2052, 2078): Physical
    -4.6 ( 14.5 )
    -4.3 ( 14.5 )
        Change at EOT (n=2262, 2287): Physical
    -4.1 ( 14.7 )
    -3.2 ( 14.9 )
        Change at FU Month 18 (n=1918, 1925): Physical
    -0.9 ( 13.5 )
    -0.9 ( 14.5 )
        Change at FU Month 24 (n=1867, 1875): Physical
    -0.4 ( 13.8 )
    -0.3 ( 14.5 )
        Change at FU Month 36 (n=1820, 1792): Physical
    -0.3 ( 14.1 )
    -0.1 ( 13.9 )
        Baseline (n=2334, 2337): Role
    79.8 ( 24.7 )
    79.4 ( 25.2 )
        Change at Week 13 (n=2075, 2111): Role
    -8.0 ( 28.6 )
    -8.5 ( 29.5 )
        Change at Week 25 (n=2049, 2073): Role
    -0.7 ( 26.4 )
    0.4 ( 27.8 )
        Change at EOT (n=2258, 2281): Role
    0.4 ( 27.8 )
    2.3 ( 28.1 )
        Change at FU Month 18 (n=1916, 1921): Role
    6.1 ( 26.5 )
    5.7 ( 28.9 )
        Change at FU Month 24 (n=1865, 1872): Role
    7.3 ( 26.8 )
    6.9 ( 28.2 )
        Change at FU Month 36 (n=1817, 1790): Role
    7.9 ( 26.4 )
    7.6 ( 27.9 )
        Baseline (n=2332, 2336): Social
    81.9 ( 22.9 )
    80.6 ( 24.1 )
        Change at Week 13 (n=2071, 2110): Social
    -8.7 ( 25.8 )
    -7.8 ( 27.1 )
        Change at Week 25 (n=2044, 2072): Social
    -2.2 ( 24.5 )
    -0.7 ( 26.3 )
        Change at EOT (n=2258, 2282): Social
    0.0 ( 25.2 )
    1.2 ( 26.3 )
        Change at FU Month 18 (n=1910, 1915): Social
    5.0 ( 23.8 )
    4.8 ( 26.7 )
        Change at FU Month 24 (n=1864, 1868): Social
    5.5 ( 24.8 )
    6.5 ( 26.6 )
        Change at FU Month 36 (n=1812, 1783): Social
    6.6 ( 24.9 )
    7.1 ( 27.3 )
        Baseline (n=2334, 2341): Cognitive
    88.8 ( 16.6 )
    87.9 ( 17.9 )
        Change at Week 13 (n=2073, 2115): Cognitive
    -9.1 ( 20.5 )
    -9.0 ( 21.4 )
        Change at Week 25 (n=2046, 2076): Cognitive
    -7.6 ( 20.4 )
    -7.0 ( 20.8 )
        Change at EOT (n=2259, 2287): Cognitive
    -7.7 ( 20.6 )
    -7.2 ( 21.4 )
        Change at FU Month 18 (n=1911, 1920): Cognitive
    -6.1 ( 19.6 )
    -5.8 ( 21.2 )
        Change at FU Month 24 (n=1865, 1870): Cognitive
    -6.2 ( 20.5 )
    -5.5 ( 21.7 )
        Change at FU Month 36 (n=1814, 1786): Cognitive
    -5.4 ( 20.6 )
    -4.9 ( 21.8 )
        Baseline (n=2332, 2340): Emotional
    72.8 ( 22.4 )
    71.3 ( 22.7 )
        Change at Week 13 (n=2071, 2114): Emotional
    3.3 ( 22.2 )
    2.9 ( 22.5 )
        Change at Week 25 (n=2044, 2076): Emotional
    5.1 ( 22.7 )
    5.9 ( 22.2 )
        Change at EOT (n=2257, 2286): Emotional
    5.6 ( 23.2 )
    6.2 ( 23.4 )
        Change at FU Month 18 (n=1909, 1918): Emotional
    7.7 ( 23.4 )
    7.6 ( 23.4 )
        Change at FU Month 24 (n=1864, 1869): Emotional
    7.8 ( 23.3 )
    8.5 ( 24.2 )
        Change at FU Month 36 (n=1812, 1785): Emotional
    7.8 ( 23.8 )
    8.4 ( 24.4 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EORTC QLQ-C30 Disease/Treatment-Related Symptoms Subscale Scores

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    End point title
    Change From Baseline in EORTC QLQ-C30 Disease/Treatment-Related Symptoms Subscale Scores
    End point description
    EORTC QLQ-C30 is a cancer-specific instrument with 30 questions used to assess overall QOL in cancer participants. First 28 questions used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much)for evaluating 5 functional scales (physical,role,social,cognitive,emotional), 8 symptom scales(diarrhea,fatigue,dyspnea,appetite loss,insomnia,nausea and vomiting[N/V],constipation,pain)and a single item(financial difficulties). Last 2 questions represented participant’s assessment of overall health and QOL, coded on 7-point scale(1=very poor to 7=excellent). EORTC QLQ-C30 disease/treatment-related symptom scores were linearly transformed on scale of 0 to 100, with high score indicating higher level of symptoms. Negative change from Baseline values indicated improvement in symptoms. ITT population. "Number of subjects analysed"=participants evaluable for this endpoint. n= participants responding to this scale where it is considered complete as defined by EORTC QLQ-C30 scoring manual.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2338
    2342
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2329, 2339):Diarrhea
    5.2 ( 14.4 )
    5.1 ( 13.5 )
        Change at Week 13 (n=2067, 2111):Diarrhea
    22.3 ( 29.8 )
    9.2 ( 23.9 )
        Change at Week 25 (n=2043, 2075):Diarrhea
    13.2 ( 26.5 )
    3.3 ( 19.8 )
        Change at EOT (n=2257, 2285):Diarrhea
    12.2 ( 26.9 )
    2.9 ( 20.0 )
        Change at FU Month 18 (n=1907, 1919):Diarrhea
    -0.5 ( 17.7 )
    0.2 ( 17.5 )
        Change at FU Month 24 (n=1861, 1868):Diarrhea
    -0.8 ( 17.4 )
    0.2 ( 18.3 )
        Change at FU Month 36 (n=1810, 1784):Diarrhea
    -0.8 ( 16.5 )
    0.3 ( 16.9 )
        Baseline (n=2335, 2341):Fatigue
    22.4 ( 19.7 )
    23.2 ( 20.5 )
        Change at Week 13 (n=2074, 2116):Fatigue
    16.1 ( 24.3 )
    16.2 ( 24.4 )
        Change at Week 25 (n=2050, 2078):Fatigue
    7.8 ( 22.5 )
    6.6 ( 22.3 )
        Change at EOT (n=2259, 2287):Fatigue
    7.1 ( 23.0 )
    5.2 ( 23.0 )
        Change at FU Month 18 (n=1914, 1924):Fatigue
    1.1 ( 21.7 )
    1.2 ( 22.5 )
        Change at FU Month 24 (n=1864, 1873):Fatigue
    0.4 ( 22.0 )
    0.4 ( 22.6 )
        Change at FU Month 36 (n=1817, 1791):Fatigue
    -0.2 ( 21.8 )
    0.6 ( 22.8 )
        Baseline (n=2331, 2336):Dyspnea
    6.8 ( 15.5 )
    8.0 ( 17.1 )
        Change at Week 13 (n=2067, 2112):Dyspnea
    12.3 ( 23.8 )
    14.6 ( 26.4 )
        Change at Week 25 (n=2045, 2073):Dyspnea
    6.3 ( 19.9 )
    6.4 ( 22.1 )
        Change at EOT (n=2254, 2283):Dyspnea
    6.6 ( 20.5 )
    6.5 ( 22.5 )
        Change at FU Month 18 (n=1911, 1917):Dyspnea
    5.9 ( 21.0 )
    5.0 ( 21.5 )
        Change at FU Month 24 (n=1860, 1870):Dyspnea
    5.1 ( 20.5 )
    5.3 ( 22.4 )
        Change at FU Month 36 (n=1814, 1783):Dyspnea
    5.1 ( 20.5 )
    5.3 ( 22.3 )
        Baseline (n=2335, 2340):Appetite Loss
    8.5 ( 18.2 )
    9.1 ( 18.7 )
        Change at Week 13 (n=2073, 2114):Appetite Loss
    13.6 ( 29.2 )
    7.7 ( 27.9 )
        Change at Week 25 (n=2049, 2078):Appetite Loss
    5.2 ( 25.1 )
    0.3 ( 22.4 )
        Change at EOT (n=2257,2286):Appetite Loss
    3.0 ( 24.5 )
    -0.9 ( 22.6 )
        Change at FU Month 18 (n=1913, 1924):Appetite Loss
    -3.0 ( 20.1 )
    -3.1 ( 21.1 )
        Change at FU Month 24 (n=1862, 1871):Appetite Loss
    -3.2 ( 20.6 )
    -3.3 ( 21.0 )
        Change at FU Month 36 (n=1817, 1789):Appetite Loss
    -3.0 ( 20.4 )
    -2.7 ( 21.2 )
        Baseline (n=2333, 2338):Insomnia
    25.3 ( 27.4 )
    27.3 ( 28.5 )
        Change at Week 13 (n=2073, 2111):Insomnia
    6.3 ( 30.3 )
    5.1 ( 32.2 )
        Change at Week 25 (n=2049, 2073):Insomnia
    4.3 ( 30.6 )
    2.0 ( 31.8 )
        Change at EOT (n=2257, 2282):Insomnia
    3.2 ( 31.0 )
    0.9 ( 32.8 )
        Change at FU Month 18 (n=1913, 1917):Insomnia
    -0.1 ( 31.1 )
    0.4 ( 32.4 )
        Change at FU Month 24 (n=1863, 1869):Insomnia
    -1.5 ( 31.3 )
    -1.1 ( 32.9 )
        Change at FU Month 36 (n=1816, 1786):Insomnia
    -0.3 ( 31.1 )
    -0.5 ( 33.5 )
        Baseline (n=2338, 2342):N/V
    2.7 ( 8.2 )
    3.1 ( 9.4 )
        Change at Week 13 (n=2077, 2118):N/V
    5.6 ( 15.7 )
    3.7 ( 14.5 )
        Change at Week 25 (n=2052, 2079):N/V
    1.1 ( 11.8 )
    0.5 ( 12.4 )
        Change at EOT (n=2261, 2288):N/V
    1.6 ( 12.7 )
    0.8 ( 13.2 )
        Change at FU Month 18 (n=1918, 1925):N/V
    -0.2 ( 10.5 )
    -0.4 ( 12.1 )
        Change at FU Month 24 (n=1865, 1874):N/V
    0.0 ( 10.7 )
    -0.1 ( 11.8 )
        Change at FU Month 36 (n=1819, 1792):N/V
    0.3 ( 11.0 )
    0.2 ( 11.7 )
        Baseline (n=2335, 2339):Constipation
    8.7 ( 19.1 )
    10.0 ( 19.8 )
        Change at Week 13 (n=2066, 2113):Constipation
    1.4 ( 23.5 )
    4.1 ( 25.6 )
        Change at Week 25 (n=2047, 2075):Constipation
    -0.7 ( 21.8 )
    0.2 ( 22.8 )
        Change at EOT (n=2256,2285):Constipation
    0.1 ( 22.4 )
    0.9 ( 23.3 )
        Change at FU Month 18 (n=1912, 1922):Constipation
    3.0 ( 23.3 )
    1.5 ( 23.8 )
        Change at FU Month 24 (n=1865, 1872):Constipation
    2.1 ( 23.1 )
    0.6 ( 22.9 )
        Change at FU Month 36 (n=1815, 1784):Constipation
    2.1 ( 22.9 )
    1.5 ( 22.7 )
        Baseline (n=2337, 2342):Pain
    18.8 ( 21.4 )
    19.6 ( 22.1 )
        Change at Week 13 (n=2077, 2118):Pain
    2.3 ( 25.4 )
    5.0 ( 26.1 )
        Change at Week 25 (n=2051, 2080):Pain
    1.4 ( 24.1 )
    1.4 ( 24.9 )
        Change at EOT (n=2261, 2288):Pain
    0.1 ( 24.7 )
    0.5 ( 25.8 )
        Change at FU Month 18 (n=1918, 1927):Pain
    -1.3 ( 23.3 )
    -0.5 ( 25.8 )
        Change at FU Month 24 (n=1868, 1874):Pain
    -1.6 ( 24.2 )
    -2.2 ( 25.6 )
        Change at FU Month 36 (n=1818, 1792):Pain
    -2.6 ( 24.4 )
    -2.3 ( 25.0 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EORTC QLQ-C30 Financial Difficulties Subscale Scores

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    End point title
    Change From Baseline in EORTC QLQ-C30 Financial Difficulties Subscale Scores
    End point description
    EORTC QLQ-C30 is a cancer-specific instrument with 30 questions used to assess overall QOL in cancer participants. First 28 questions used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much)for evaluating 5 functional scales (physical,role,social,cognitive,emotional), 8 symptom scales(diarrhea fatigue,dyspnea,appetite loss,insomnia,N/V,constipation,pain)and a single item(financial difficulties). Last 2 questions represented participant’s assessment of overall health and quality of life, coded on 7-point scale(1=very poor to 7=excellent). Financial difficulties scores were linearly transformed on a scale of 0 and 100, with a high score indicating a higher level of financial difficulties. Negative change from Baseline values indicated improvement in financial difficulties. ITT population."Number of subjects analysed"=participants evaluable for this endpoint. n= participants responding to this scale where it is considered complete as defined by EORTC QLQ-C30 scoring manual.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2319
    2334
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2319, 2334)
    20.3 ( 28.7 )
    22.1 ( 30.0 )
        Change at Week 13 (n=2052, 2103)
    3.1 ( 26.1 )
    1.7 ( 27.0 )
        Change at Week 25 (n=2025, 2067)
    2.3 ( 26.8 )
    -0.3 ( 26.9 )
        Change at EOT (n=2244, 2280)
    -0.2 ( 27.6 )
    -1.5 ( 27.2 )
        Change at FU Month 18 (n=1894, 1912)
    -4.1 ( 27.9 )
    -5.1 ( 27.5 )
        Change at FU Month 24 (n=1852, 1866)
    -5.2 ( 28.6 )
    -6.9 ( 29.3 )
        Change at FU Month 36 (n=1798, 1781)
    -7.1 ( 28.5 )
    -8.3 ( 28.3 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer - Breast Cancer Module Quality of Life (EORTC QLQ-BR23) Functional Scale Score

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    End point title
    Change From Baseline in European Organisation for Research and Treatment of Cancer - Breast Cancer Module Quality of Life (EORTC QLQ-BR23) Functional Scale Score
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of 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. Negative change from Baseline indicated deterioration in QOL and positive change from Baseline indicated an improvement in QOL. ITT population. "Number of subjects analysed"=participants evaluable for this endpoint. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2313
    2318
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2313, 2317):Body Image
    79.7 ( 23.5 )
    78.9 ( 23.7 )
        Change at Week 13 (n=2048, 2086): Body Image
    -12.9 ( 24.7 )
    -13.9 ( 25.2 )
        Change at Week 25 (n=2020, 2050): Body Image
    -7.6 ( 23.8 )
    -7.3 ( 23.4 )
        Change at EOT (n=2237, 2261):Body Image
    -4.9 ( 23.7 )
    -6.0 ( 24.6 )
        Change at FU Month 18 (n=1887, 1889):Body Image
    -0.1 ( 23.3 )
    -1.3 ( 23.3 )
        Change at FU Month 24 (n=1839, 1852):Body Image
    0.5 ( 23.6 )
    0.1 ( 23.5 )
        Change at FU Month 36 (n=1789, 1758):Body Image
    1.7 ( 24.4 )
    0.7 ( 24.6 )
        Baseline (n=966, 997):Sexual Enjoyment
    54.0 ( 30.8 )
    55.0 ( 30.7 )
        Change at Week 13 (n=530, 553): Sexual Enjoyment
    -16.5 ( 28.4 )
    -13.1 ( 27.2 )
        Change at Week 25 (n=558, 630): Sexual Enjoyment
    -11.9 ( 26.8 )
    -7.9 ( 26.5 )
        Change at EOT (n=781, 820):Sexual Enjoyment
    -10.7 ( 27.5 )
    -8.0 ( 27.7 )
        Change at FU Month 18(n=585, 581):Sexual Enjoyment
    -4.2 ( 28.5 )
    -6.7 ( 26.5 )
        Change at FU Month 24(n=576, 561):Sexual Enjoyment
    -6.0 ( 28.4 )
    -5.0 ( 27.6 )
        Change at FU Month 36(n=530, 541):Sexual Enjoyment
    -5.3 ( 28.1 )
    -6.0 ( 26.8 )
        Baseline (n=2258, 2260):Sexual Function
    19.6 ( 23.8 )
    20.8 ( 24.3 )
        Change at Week 13 (n=1969, 2008): Sexual Function
    -5.6 ( 20.5 )
    -6.6 ( 20.7 )
        Change at Week 25 (n=1945, 1975): Sexual Function
    -2.6 ( 20.8 )
    -2.3 ( 20.9 )
        Change at EOT (n=2176,2191):Sexual Function
    -1.0 ( 20.8 )
    -1.4 ( 21.2 )
        Change at FU Month 18(n=1814,1820):Sexual Function
    2.5 ( 22.8 )
    1.4 ( 21.7 )
        Change at FU Month 24(n=1757,1778):Sexual Function
    2.8 ( 22.9 )
    1.8 ( 22.7 )
        Change at FU Month 36(n=1711,1685):Sexual Function
    2.6 ( 24.0 )
    1.6 ( 23.6 )
        Baseline (n=2312, 2318):FP
    51.3 ( 31.7 )
    50.5 ( 31.5 )
        Change at Week 13 (n=2043, 2090): FP
    3.1 ( 30.2 )
    1.8 ( 31.9 )
        Change at Week 25 (n=2020, 2052): FP
    6.3 ( 31.1 )
    5.4 ( 31.2 )
        Change at EOT (n=2238, 2263): FP
    7.7 ( 32.2 )
    6.9 ( 31.8 )
        Change at FU Month 18 (n=1887, 1884):FP
    12.9 ( 32.2 )
    10.5 ( 32.0 )
        Change at FU Month 24 (n=1836, 1849):FP
    13.7 ( 32.9 )
    12.9 ( 32.9 )
        Change at FU Month 36 (n=1785, 1752):FP
    14.7 ( 34.1 )
    13.6 ( 32.9 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EORTC QLQ-BR23 Symptom Scale Score

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    End point title
    Change From Baseline in EORTC QLQ-BR23 Symptom Scale Score
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of 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 symptom scale indicated high level of symptomatology/problems/greater degree of symptoms. Negative change from Baseline indicated deterioration in QOL and positive change from Baseline indicated an improvement in QOL. ITT population. "Number of subjects analysed"=participants evaluable for this endpoint. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2331
    2335
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2331, 2335):Systemic SE
    9.5 ( 10.9 )
    10.2 ( 11.2 )
        Change at Week 13 (n=2071, 2107): Systemic SE
    21.1 ( 17.5 )
    21.7 ( 17.9 )
        Change at Week 25 (n=2043, 2072): Systemic SE
    9.2 ( 14.2 )
    8.2 ( 14.2 )
        Change at EOT (n=2258, 2280)
    8.3 ( 15.4 )
    7.5 ( 14.8 )
        Change at FU Month 18 (n=1909, 1912):Systemic SE
    4.4 ( 12.8 )
    5.5 ( 13.4 )
        Change at FU Month 24 (n=1860, 1871):Systemic SE
    4.1 ( 13.2 )
    4.9 ( 13.7 )
        Change at FU Month 36 (n=1812, 1783):Systemic SE
    4.5 ( 13.6 )
    5.2 ( 13.8 )
        Baseline (n=356, 340): Hair Loss
    26.4 ( 32.8 )
    22.1 ( 29.0 )
        Change at Week 13 (n=208, 206): Hair Loss
    17.3 ( 43.6 )
    21.2 ( 37.8 )
        Change at Week 25 (n=100, 101): Hair Loss
    8.3 ( 38.0 )
    14.5 ( 38.4 )
        Change at EOT (n=297, 290): Hair Loss
    10.9 ( 40.1 )
    17.9 ( 39.8 )
        Change at FU Month 18 (n=71, 104): Hair Loss
    -7.0 ( 36.0 )
    3.2 ( 34.9 )
        Change at FU Month 24 (n=73, 92): Hair Loss
    -4.1 ( 39.3 )
    0.7 ( 36.0 )
        Change at FU Month 36 (n=95, 111): Hair Loss
    -5.6 ( 42.3 )
    2.4 ( 34.7 )
        Baseline (n=2326, 2331): Arm Symptoms
    21.6 ( 19.1 )
    21.7 ( 19.2 )
        Change at Week 13 (n=2064, 2102): Arm Symptoms
    -4.7 ( 20.8 )
    -2.1 ( 21.5 )
        Change at Week 25 (n=2037, 2070): Arm Symptoms
    -2.9 ( 21.3 )
    -2.3 ( 21.7 )
        Change at EOT (n=2251,2275):Arm Symptoms
    -3.5 ( 21.5 )
    -3.4 ( 21.4 )
        Change at FU Month 18 (n=1903, 1913):Arm Symptoms
    -4.0 ( 21.8 )
    -3.9 ( 22.5 )
        Change at FU Month 24 (n=1857, 1866):Arm Symptoms
    -5.1 ( 21.6 )
    -5.0 ( 22.3 )
        Change at FU Month 36 (n=1809, 1777):Arm Symptoms
    -5.9 ( 21.8 )
    -4.7 ( 22.4 )
        Baseline (n=2325, 2330): Breast Symptoms
    19.5 ( 17.5 )
    20.4 ( 17.7 )
        Change at Week 13 (n=2063, 2102): Breast Symptoms
    -5.0 ( 18.4 )
    -5.2 ( 18.0 )
        Change at Week 25 (n=2036, 2069): Breast Symptoms
    1.9 ( 20.7 )
    -0.4 ( 20.6 )
        Change at EOT (n=2250,2275):Breast Symptoms
    -0.6 ( 20.2 )
    -3.8 ( 19.7 )
        Change at FU Month 18(n=1903,1911):Breast Symptoms
    -3.0 ( 18.7 )
    -5.9 ( 18.8 )
        Change at FU Month 24(n=1857,1865):Breast Symptoms
    -6.4 ( 18.4 )
    -7.3 ( 18.7 )
        Change at FU Month 36(n=1808,1775):Breast Symptoms
    -7.3 ( 18.8 )
    -7.9 ( 19.0 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response for European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Mobility Domain

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    End point title
    Percentage of Participants With Response for European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Questionnaire: Mobility Domain
    End point description
    EQ-5D-3L is a descriptive system of health-related quality of life states consisting of 5 dimensions/domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each of which has 3 levels of severity (no problems [scored as 1], some or moderate problems [scored as 2], and extreme problems [scored as 3]). Percentage of participants with each of the following responses in mobility domain was reported: I have no problems in walking about; I have some problems in walking about; and I am confined to bed. Response percentages may not add up to 100% due to data rounding. ITT population. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
    number (not applicable)
        Baseline (n=2292, 2310): No problems
    93.8
    92.9
        Baseline (n=2292, 2310): Some problems
    6.2
    6.9
        Baseline (n=2292, 2310): Confined to bed
    0.0
    0.2
        Week 13 (n=2080, 2129): No problems
    77.5
    74.8
        Week 13 (n=2080, 2129): Some problems
    22.1
    24.8
        Week 13 (n=2080, 2129): Confined to bed
    0.4
    0.4
        Week 25 (n=2062, 2081): No problems
    83.8
    82.7
        Week 25 (n=2062, 2081): Some problems
    16.1
    17.2
        Week 25 (n=2062, 2081): Confined to bed
    0.1
    0.1
        EOT (n=2051, 2106): No problems
    85.1
    84.9
        EOT (n=2051, 2106): Some problems
    14.8
    14.9
        EOT (n=2051, 2106): Confined to bed
    0.1
    0.2
        FU Month 18 (n=1920, 1919): No problems
    88.8
    87.0
        FU Month 18 (n=1920, 1919): Some problems
    11.2
    12.8
        FU Month 18 (n=1920, 1919): Confined to bed
    0.1
    0.2
        FU Month 24 (n=1864, 1877): No problems
    87.8
    87.7
        FU Month 24 (n=1864, 1877): Some problems
    12.1
    12.1
        FU Month 24 (n=1864, 1877): Confined to bed
    0.1
    0.1
        FU Month 36 (n=1822, 1795): No problems
    88.5
    87.8
        FU Month 36 (n=1822, 1795): Some problems
    11.5
    12.1
        FU Month 36 (n=1822, 1795): Confined to bed
    0.0
    0.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response for EQ-5D-3L Questionnaire: Self-Care Domain

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    End point title
    Percentage of Participants With Response for EQ-5D-3L Questionnaire: Self-Care Domain
    End point description
    EQ-5D-3L is a descriptive system of health-related quality of life states consisting of 5 dimensions/domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each of which has 3 levels of severity (no problems [scored as 1], some or moderate problems [scored as 2], and extreme problems [scored as 3]). Percentage of participants with each of the following responses in self-care domain was reported: I have no problems with self-care; I have some problems washing or dressing myself; and I am unable to wash or dress myself. Response percentages may not add up to 100% due to data rounding. ITT population. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
    number (not applicable)
        Baseline (n=2289, 2310): No problems
    89.7
    90.7
        Baseline (n=2289, 2310): Some problems
    10.0
    9.1
        Baseline (n=2289, 2310): Unable
    0.3
    0.2
        Week 13 (n=2079, 2127): No problems
    94.3
    93.2
        Week 13 (n=2079, 2127): Some problems
    5.3
    6.4
        Week 13 (n=2079, 2127): Unable
    0.4
    0.4
        Week 25 (n=2057, 2077): No problems
    95.5
    95.0
        Week 25 (n=2057, 2077): Some problems
    4.3
    4.7
        Week 25 (n=2057, 2077): Unable
    0.1
    0.3
        EOT (n=2051, 2106): No problems
    95.4
    95.8
        EOT (n=2051, 2106): Some problems
    4.4
    4.0
        EOT (n=2051, 2106): Unable
    0.2
    0.2
        FU Month 18 (n=1917, 1921): No problems
    97.2
    96.0
        FU Month 18 (n=1917, 1921): Some problems
    2.6
    3.6
        FU Month 18 (n=1917, 1921): Unable
    0.2
    0.3
        FU Month 24 (n=1861, 1877): No problems
    96.9
    96.3
        FU Month 24 (n=1861, 1877): Some problems
    2.8
    3.5
        FU Month 24 (n=1861, 1877): Unable
    0.3
    0.3
        FU Month 36 (n=1822, 1794): No problems
    97.3
    96.5
        FU Month 36 (n=1822, 1794): Some problems
    2.5
    3.2
        FU Month 36 (n=1822, 1794): Unable
    0.2
    0.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response for EQ-5D-3L Questionnaire: Usual Activities Domain

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    End point title
    Percentage of Participants With Response for EQ-5D-3L Questionnaire: Usual Activities Domain
    End point description
    EQ-5D-3L is a descriptive system of health-related quality of life states consisting of 5 dimensions/domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each of which has 3 levels of severity (no problems [scored as 1], some or moderate problems [scored as 2], and extreme problems [scored as 3]). Percentage of participants with each of the following responses in usual activities domain was reported: I have no problems with performing my usual activities; I have some problems with performing my usual activities; and I am unable to perform my usual activities. Response percentages may not add up to 100% due to data rounding. ITT population. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
    number (not applicable)
        Baseline (n=2288, 2308): No problems
    67.4
    66.1
        Baseline (n=2288, 2308): Some problems
    30.4
    32.2
        Baseline (n=2288, 2308): Unable
    2.2
    1.7
        Week 13 (n=2078, 2128): No problems
    56.8
    54.1
        Week 13 (n=2078, 2128): Some problems
    40.1
    43.0
        Week 13 (n=2078, 2128): Unable
    3.1
    2.9
        Week 25 (n=2059, 2077): No problems
    66.5
    65.8
        Week 25 (n=2059, 2077): Some problems
    32.2
    32.7
        Week 25 (n=2059, 2077): Unable
    1.2
    1.4
        EOT (n=2049, 2102): No problems
    72.4
    72.5
        EOT (n=2049, 2102): Some problems
    26.3
    26.6
        EOT (n=2049, 2102): Unable
    1.3
    0.9
        FU Month 18 (n=1919, 1918): No problems
    78.5
    76.3
        FU Month 18 (n=1919, 1918): Some problems
    20.6
    23.0
        FU Month 18 (n=1919, 1918): Unable
    0.9
    0.7
        FU Month 24 (n=1862, 1875): No problems
    78.7
    79.1
        FU Month 24 (n=1862, 1875): Some problems
    20.4
    19.7
        FU Month 24 (n=1862, 1875): Unable
    0.9
    1.1
        FU Month 36 (n=1821, 1794): No problems
    80.9
    79.8
        FU Month 36 (n=1821, 1794): Some problems
    18.3
    19.4
        FU Month 36 (n=1821, 1794): Unable
    0.7
    0.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response for EQ-5D-3L Questionnaire: Pain/Discomfort Domain

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    End point title
    Percentage of Participants With Response for EQ-5D-3L Questionnaire: Pain/Discomfort Domain
    End point description
    EQ-5D-3L is a descriptive system of health-related quality of life states consisting of 5 dimensions/domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each of which has 3 levels of severity (no problems [scored as 1], some or moderate problems [scored as 2], and extreme problems [scored as 3]). Percentage of participants with each of the following responses in pain/discomfort domain was reported: I have no pain or discomfort; I have moderate pain or discomfort; and I have extreme pain or discomfort. Response percentages may not add up to 100% due to data rounding. ITT population. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
    number (not applicable)
        Baseline (n=2290, 2310): No pain/discomfort
    49.0
    49.0
        Baseline (n=2290, 2310): Moderate pain/discomfort
    50.0
    49.7
        Baseline (n=2290, 2310): Extreme pain/discomfort
    1.0
    1.3
        Week 13 (n=2076, 2127): No pain/discomfort
    44.6
    40.5
        Week 13 (n=2076, 2127): Moderate pain/discomfort
    52.7
    56.5
        Week 13 (n=2076, 2127): Extreme pain/discomfort
    2.7
    3.0
        Week 25 (n=2062, 2080): No pain/discomfort
    44.3
    43.7
        Week 25 (n=2062, 2080): Moderate pain/discomfort
    53.3
    54.4
        Week 25 (n=2062, 2080): Extreme pain/discomfort
    2.4
    1.9
        EOT (n=2049, 2106): No pain/discomfort
    49.3
    50.0
        EOT (n=2049, 2106): Moderate pain/discomfort
    48.5
    47.6
        EOT (n=2049, 2106): Extreme pain/discomfort
    2.2
    2.4
        FU Month 18 (n=1918, 1918): No pain/discomfort
    51.3
    53.1
        FU Month 18(n=1918, 1918):Moderate pain/discomfort
    46.6
    44.7
        FU Month 18(n=1918, 1918):Extreme pain/discomfort
    2.1
    2.1
        FU Month 24 (n=1863, 1879): No pain/discomfort
    56.7
    56.0
        FU Month 24(n=1863, 1879):Moderate pain/discomfort
    41.3
    41.5
        FU Month 24(n=1863, 1879):Extreme pain/discomfort
    1.9
    2.5
        FU Month 36 (n=1823, 1793): No pain/discomfort
    59.5
    57.8
        FU Month 36(n=1823, 1793):Moderate pain/discomfort
    38.9
    40.1
        FU Month 36(n=1823, 1793):Extreme pain/discomfort
    1.6
    2.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response for EQ-5D-3L Questionnaire: Anxiety/Depression Domain

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    End point title
    Percentage of Participants With Response for EQ-5D-3L Questionnaire: Anxiety/Depression Domain
    End point description
    EQ-5D-3L is a descriptive system of health-related quality of life states consisting of 5 dimensions/domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and each of which has 3 levels of severity (no problems [scored as 1], some or moderate problems [scored as 2], and extreme problems [scored as 3]). Percentage of participants with each of the following responses in anxiety/depression domain was reported: I am not anxious or depressed; I am moderately anxious or depressed; and I am extremely anxious or depressed. Response percentages may not add up to 100% due to data rounding. ITT population. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 13, 25; EOT (28 days after the last dose, up to Week 56); FU Months 18, 24, 36
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    2400
    2404
    Units: percentage of participants
    number (not applicable)
        Baseline (n=2286, 2310): Not anxious/depress
    47.1
    44.7
        Baseline (n=2286, 2310): Moderate anxious/depress
    49.4
    50.1
        Baseline (n=2286, 2310): Extreme anxious/depress
    3.5
    5.2
        Week 13 (n=2076, 2125): Not anxious/depress
    53.6
    52.4
        Week 13 (n=2076, 2125): Moderate anxious/depress
    43.4
    44.0
        Week 13 (n=2076, 2125): Extreme anxious/depress
    3.0
    3.7
        Week 25 (n=2060, 2075): Not anxious/depress
    55.5
    55.5
        Week 25 (n=2060, 2075): Moderate anxious/depress
    41.9
    41.8
        Week 25 (n=2060, 2075): Extreme anxious/depress
    2.5
    2.7
        EOT (n=2041,2101):Not anxious/depress
    58.5
    58.3
        EOT (n=2041, 2101): Moderate anxious/depress
    38.9
    39.1
        EOT (n=2041, 2101): Extreme anxious/depress
    2.6
    2.6
        FU Month 18(n=1916,1915):Not anxious/depress
    61.4
    59.9
        FU Month 18(n=1916,1915):Moderate anxious/depress
    36.2
    37.0
        FU Month 18(n=1916,1915):Extreme anxious/depress
    2.4
    3.1
        FU Month 24(n=1860,1872):Not anxious/depress
    63.8
    61.0
        FU Month 24(n=1860,1872):Moderate anxious/depress
    33.8
    36.2
        FU Month 24(n=1860,1872):Extreme anxious/depress
    2.4
    2.8
        FU Month 36(n=1815,1787):Not anxious/depress
    64.0
    61.6
        FU Month 36(n=1815,1787):Moderate anxious/depress
    33.3
    35.4
        FU Month 36(n=1815,1787):Extreme anxious/depress
    2.6
    3.0
    No statistical analyses for this end point

    Secondary: Trough Serum Concentration (Cmin) of Pertuzumab

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    End point title
    Trough Serum Concentration (Cmin) of Pertuzumab
    End point description
    Pharmacokinetic (PK) evaluable participants were defined as those who received at least one active pertuzumab and/or trastuzumab treatment and had at least one PK sample collected. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 10 and 15 (Cycle length=21 days)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy
    Number of subjects analysed
    36
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 (n=31)
    68.0 ( 16.6 )
        Cycle 10 (n=31)
    88.1 ( 34.4 )
        Cycle 15 (n=27)
    95.5 ( 51.5 )
    No statistical analyses for this end point

    Secondary: Cmin of Trastuzumab

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    End point title
    Cmin of Trastuzumab
    End point description
    PK evaluable participants. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 10 and 15 (Cycle length=21 days)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    36
    34
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=32, 31)
    32.1 ( 13.4 )
    34.1 ( 11.4 )
        Cycle 10 (n=33, 26)
    65.0 ( 39.6 )
    68.4 ( 23.0 )
        Cycle 15 (n=27, 22)
    72.9 ( 46.1 )
    71.0 ( 30.4 )
    No statistical analyses for this end point

    Secondary: Peak Serum Concentration (Cmax) of Pertuzumab

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    End point title
    Peak Serum Concentration (Cmax) of Pertuzumab
    End point description
    PK evaluable participants. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 10 and 15 (Cycle length=21 days)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy
    Number of subjects analysed
    36
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=33)
    237 ( 118 )
        Cycle 10 (n=29)
    222 ( 92.2 )
        Cycle 15 (n=24)
    206 ( 94.9 )
    No statistical analyses for this end point

    Secondary: Cmax of Trastuzumab

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    End point title
    Cmax of Trastuzumab
    End point description
    PK evaluable participants. Here, n=participants evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 10 and 15 (Cycle length=21 days)
    End point values
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    36
    34
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 (n=36, 33)
    180 ( 81.0 )
    190 ( 51.6 )
        Cycle 10 (n=33, 27)
    219 ( 94.6 )
    225 ( 70.7 )
        Cycle 15 (n=25, 21)
    187 ( 95.1 )
    234 ( 73.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization until data cut-off date 19 December 2016 (up to maximum length of follow-up of 59 months)
    Adverse event reporting additional description
    Safety population. 38 participants randomized to pertuzumab arm received study treatment but did not receive pertuzumab and were included in the placebo arm for safety analyses. 24 participants randomized to placebo arm received at least 1 dose of pertuzumab and were included in pertuzumab arm for safety analyses.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Chemotherapy
    Reporting group description
    Participants received pertuzumab (840 mg loading dose, then 420 mg) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 mg).

    Reporting group title
    Placebo + Trastuzumab + Chemotherapy
    Reporting group description
    Participants received placebo matched to pertuzumab IV Q3W and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) IV Q3W for 1 year (maximum 18 cycles) in combination with 1 of the following IV chemotherapy regimen (anthracycline-based or nonanthracycline-based) per Investigator's choice: 1) 3-4 cycles (Q3W) of 5-fluorouracil 500-600 mg/m^2 + epirubicin 90-120 mg/m^2 or doxorubicin 50 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W (100 mg/m^2 for 3 cycles, 75 mg/m^2 in first cycle and 100 mg/m^2 in subsequent cycles, or 75 mg/m^2 for 4 cycles) or 12 cycles of paclitaxel 80 mg/m^2 QW; 2) 4 cycles (Q3W) of doxorubicin 60 mg/m^2 or epirubicin 90-120 mg/m^2 + cyclophosphamide 500-600 mg/m^2 followed by either 3-4 cycles of docetaxel Q3W or 12 cycles of paclitaxel QW (as described in Option 1); 3) 6 cycles (Q3W) of docetaxel 75 mg/m^2 + carboplatin AUC 6 (up to 900 mg).

    Serious adverse events
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    692 / 2364 (29.27%)
    585 / 2405 (24.32%)
         number of deaths (all causes)
    73
    95
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    1 / 2364 (0.04%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric neoplasm
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric cancer
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurilemmoma benign
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic neoplasm
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Axillary vein thrombosis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         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
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    3 / 2364 (0.13%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         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 / 2364 (0.04%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 2364 (0.08%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         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
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 2364 (0.00%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 2364 (0.17%)
    6 / 2405 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    7 / 2364 (0.30%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    5 / 10
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 2364 (0.21%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 2364 (0.13%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mass
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    4 / 2364 (0.17%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    39 / 2364 (1.65%)
    45 / 2405 (1.87%)
         occurrences causally related to treatment / all
    11 / 40
    9 / 52
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 2364 (0.04%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    3 / 2364 (0.13%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    11 / 2364 (0.47%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    6 / 11
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast inflammation
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical polyp
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic cyst
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (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
    Asthma
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 2364 (0.08%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 2364 (0.25%)
    7 / 2405 (0.29%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 2364 (0.13%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung consolidation
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal oedema
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (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
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 2364 (0.08%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 2364 (0.04%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 2364 (0.21%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusional disorder, unspecified type
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    5 / 2364 (0.21%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reactive psychosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 2364 (0.13%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device extrusion
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    11 / 2364 (0.47%)
    7 / 2405 (0.29%)
         occurrences causally related to treatment / all
    11 / 12
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    7 / 2364 (0.30%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    3 / 8
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft thrombosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus facture
         subjects affected / exposed
    5 / 2364 (0.21%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    3 / 2364 (0.13%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoconiosis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (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 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary radiation injury
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         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 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    3 / 2364 (0.13%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 2364 (0.00%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    3 / 2364 (0.13%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 2364 (0.13%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    33 / 2364 (1.40%)
    17 / 2405 (0.71%)
         occurrences causally related to treatment / all
    32 / 35
    16 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic cardiomyopathy
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 2364 (0.17%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    3 / 2364 (0.13%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial neuralgia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head titubation
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         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 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 2364 (0.13%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sunct syndrome
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    13 / 2364 (0.55%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    2 / 13
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    10 / 2364 (0.42%)
    8 / 2405 (0.33%)
         occurrences causally related to treatment / all
    7 / 13
    5 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    2 / 2364 (0.08%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    9 / 2364 (0.38%)
    7 / 2405 (0.29%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    208 / 2364 (8.80%)
    196 / 2405 (8.15%)
         occurrences causally related to treatment / all
    27 / 233
    18 / 215
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 2364 (0.13%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathic haemolytic anaemia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    26 / 2364 (1.10%)
    32 / 2405 (1.33%)
         occurrences causally related to treatment / all
    3 / 31
    3 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 2364 (0.08%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    External ear inflammation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    5 / 2364 (0.21%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic nerve disorder
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 2364 (0.25%)
    7 / 2405 (0.29%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    4 / 2364 (0.17%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 2364 (0.08%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    4 / 2364 (0.17%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    58 / 2364 (2.45%)
    18 / 2405 (0.75%)
         occurrences causally related to treatment / all
    26 / 65
    8 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia strangulated
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    18 / 2364 (0.76%)
    14 / 2405 (0.58%)
         occurrences causally related to treatment / all
    2 / 18
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema mouth
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    4 / 2364 (0.17%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    7 / 2364 (0.30%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    19 / 2364 (0.80%)
    15 / 2405 (0.62%)
         occurrences causally related to treatment / all
    1 / 20
    2 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    5 / 2364 (0.21%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 2364 (0.21%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid disorder
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    2 / 2364 (0.08%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess oral
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatitis B
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 2364 (0.13%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    7 / 2364 (0.30%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    14 / 2364 (0.59%)
    12 / 2405 (0.50%)
         occurrences causally related to treatment / all
    2 / 14
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    7 / 2364 (0.30%)
    9 / 2405 (0.37%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    3 / 2364 (0.13%)
    6 / 2405 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 2364 (0.13%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    8 / 2364 (0.34%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (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
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    7 / 2364 (0.30%)
    6 / 2405 (0.25%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 2364 (0.17%)
    3 / 2405 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 2364 (0.13%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphangitis
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    4 / 2364 (0.17%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    3 / 2364 (0.13%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    10 / 2364 (0.42%)
    4 / 2405 (0.17%)
         occurrences causally related to treatment / all
    3 / 11
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis infective
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 2364 (0.68%)
    23 / 2405 (0.96%)
         occurrences causally related to treatment / all
    4 / 16
    2 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         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 / 2364 (0.08%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 2364 (0.30%)
    9 / 2405 (0.37%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 2364 (0.00%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Serratia infection
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 2364 (0.08%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    3 / 2364 (0.13%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 2364 (0.38%)
    8 / 2405 (0.33%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    8 / 2364 (0.34%)
    9 / 2405 (0.37%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 2364 (0.08%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    5 / 2364 (0.21%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 2364 (0.25%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    5 / 2364 (0.21%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    18 / 2364 (0.76%)
    5 / 2405 (0.21%)
         occurrences causally related to treatment / all
    4 / 18
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (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
    2 / 2364 (0.08%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    8 / 2364 (0.34%)
    2 / 2405 (0.08%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    0 / 2405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 2364 (0.04%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 2364 (0.00%)
    1 / 2405 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2350 / 2364 (99.41%)
    2370 / 2405 (98.54%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    482 / 2364 (20.39%)
    509 / 2405 (21.16%)
         occurrences all number
    520
    564
    Hypertension
         subjects affected / exposed
    91 / 2364 (3.85%)
    122 / 2405 (5.07%)
         occurrences all number
    103
    130
    Lymphoedema
         subjects affected / exposed
    133 / 2364 (5.63%)
    160 / 2405 (6.65%)
         occurrences all number
    136
    166
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    504 / 2364 (21.32%)
    499 / 2405 (20.75%)
         occurrences all number
    930
    904
    Fatigue
         subjects affected / exposed
    1150 / 2364 (48.65%)
    1063 / 2405 (44.20%)
         occurrences all number
    1764
    1617
    Influenza like illness
         subjects affected / exposed
    125 / 2364 (5.29%)
    119 / 2405 (4.95%)
         occurrences all number
    156
    148
    Mucosal inflammation
         subjects affected / exposed
    549 / 2364 (23.22%)
    447 / 2405 (18.59%)
         occurrences all number
    744
    586
    Oedema
         subjects affected / exposed
    139 / 2364 (5.88%)
    156 / 2405 (6.49%)
         occurrences all number
    160
    176
    Oedema peripheral
         subjects affected / exposed
    405 / 2364 (17.13%)
    483 / 2405 (20.08%)
         occurrences all number
    489
    580
    Pain
         subjects affected / exposed
    157 / 2364 (6.64%)
    165 / 2405 (6.86%)
         occurrences all number
    186
    200
    Pyrexia
         subjects affected / exposed
    446 / 2364 (18.87%)
    433 / 2405 (18.00%)
         occurrences all number
    633
    607
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    372 / 2364 (15.74%)
    349 / 2405 (14.51%)
         occurrences all number
    466
    434
    Dyspnoea
         subjects affected / exposed
    279 / 2364 (11.80%)
    272 / 2405 (11.31%)
         occurrences all number
    327
    320
    Epistaxis
         subjects affected / exposed
    428 / 2364 (18.10%)
    325 / 2405 (13.51%)
         occurrences all number
    513
    412
    Oropharyngeal pain
         subjects affected / exposed
    215 / 2364 (9.09%)
    175 / 2405 (7.28%)
         occurrences all number
    256
    202
    Rhinorrhoea
         subjects affected / exposed
    191 / 2364 (8.08%)
    135 / 2405 (5.61%)
         occurrences all number
    210
    150
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    151 / 2364 (6.39%)
    109 / 2405 (4.53%)
         occurrences all number
    165
    112
    Insomnia
         subjects affected / exposed
    404 / 2364 (17.09%)
    400 / 2405 (16.63%)
         occurrences all number
    454
    454
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    220 / 2364 (9.31%)
    242 / 2405 (10.06%)
         occurrences all number
    280
    322
    Aspartate aminotransferase increased
         subjects affected / exposed
    145 / 2364 (6.13%)
    162 / 2405 (6.74%)
         occurrences all number
    176
    214
    Ejection fraction decreased
         subjects affected / exposed
    115 / 2364 (4.86%)
    142 / 2405 (5.90%)
         occurrences all number
    129
    154
    Neutrophil count decreased
         subjects affected / exposed
    324 / 2364 (13.71%)
    329 / 2405 (13.68%)
         occurrences all number
    690
    695
    Weight decreased
         subjects affected / exposed
    191 / 2364 (8.08%)
    76 / 2405 (3.16%)
         occurrences all number
    202
    81
    Weight increased
         subjects affected / exposed
    59 / 2364 (2.50%)
    130 / 2405 (5.41%)
         occurrences all number
    61
    140
    White blood cell count decreased
         subjects affected / exposed
    233 / 2364 (9.86%)
    206 / 2405 (8.57%)
         occurrences all number
    561
    476
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    297 / 2364 (12.56%)
    266 / 2405 (11.06%)
         occurrences all number
    306
    270
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    269 / 2364 (11.38%)
    274 / 2405 (11.39%)
         occurrences all number
    347
    358
    Dysgeusia
         subjects affected / exposed
    614 / 2364 (25.97%)
    518 / 2405 (21.54%)
         occurrences all number
    736
    666
    Headache
         subjects affected / exposed
    531 / 2364 (22.46%)
    561 / 2405 (23.33%)
         occurrences all number
    786
    800
    Neuropathy peripheral
         subjects affected / exposed
    365 / 2364 (15.44%)
    369 / 2405 (15.34%)
         occurrences all number
    424
    417
    Paraesthesia
         subjects affected / exposed
    276 / 2364 (11.68%)
    239 / 2405 (9.94%)
         occurrences all number
    337
    277
    Peripheral sensory neuropathy
         subjects affected / exposed
    426 / 2364 (18.02%)
    422 / 2405 (17.55%)
         occurrences all number
    503
    485
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    648 / 2364 (27.41%)
    553 / 2405 (22.99%)
         occurrences all number
    794
    688
    Leukopenia
         subjects affected / exposed
    214 / 2364 (9.05%)
    220 / 2405 (9.15%)
         occurrences all number
    452
    476
    Neutropenia
         subjects affected / exposed
    574 / 2364 (24.28%)
    538 / 2405 (22.37%)
         occurrences all number
    998
    944
    Eye disorders
    Dry eye
         subjects affected / exposed
    140 / 2364 (5.92%)
    112 / 2405 (4.66%)
         occurrences all number
    145
    116
    Lacrimation increased
         subjects affected / exposed
    310 / 2364 (13.11%)
    322 / 2405 (13.39%)
         occurrences all number
    332
    344
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    281 / 2364 (11.89%)
    255 / 2405 (10.60%)
         occurrences all number
    363
    328
    Abdominal pain upper
         subjects affected / exposed
    241 / 2364 (10.19%)
    217 / 2405 (9.02%)
         occurrences all number
    298
    292
    Constipation
         subjects affected / exposed
    681 / 2364 (28.81%)
    758 / 2405 (31.52%)
         occurrences all number
    1014
    1107
    Diarrhoea
         subjects affected / exposed
    1657 / 2364 (70.09%)
    1078 / 2405 (44.82%)
         occurrences all number
    3346
    1772
    Dry mouth
         subjects affected / exposed
    148 / 2364 (6.26%)
    136 / 2405 (5.65%)
         occurrences all number
    164
    172
    Gastrooesophageal reflux disease
         subjects affected / exposed
    120 / 2364 (5.08%)
    107 / 2405 (4.45%)
         occurrences all number
    140
    119
    Haemorrhoids
         subjects affected / exposed
    183 / 2364 (7.74%)
    124 / 2405 (5.16%)
         occurrences all number
    215
    138
    Nausea
         subjects affected / exposed
    1628 / 2364 (68.87%)
    1571 / 2405 (65.32%)
         occurrences all number
    2926
    2875
    Stomatitis
         subjects affected / exposed
    665 / 2364 (28.13%)
    572 / 2405 (23.78%)
         occurrences all number
    996
    827
    Vomiting
         subjects affected / exposed
    761 / 2364 (32.19%)
    725 / 2405 (30.15%)
         occurrences all number
    1213
    1170
    Dyspepsia
         subjects affected / exposed
    325 / 2364 (13.75%)
    341 / 2405 (14.18%)
         occurrences all number
    376
    407
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1577 / 2364 (66.71%)
    1610 / 2405 (66.94%)
         occurrences all number
    1585
    1622
    Dry skin
         subjects affected / exposed
    311 / 2364 (13.16%)
    268 / 2405 (11.14%)
         occurrences all number
    346
    291
    Erythema
         subjects affected / exposed
    234 / 2364 (9.90%)
    214 / 2405 (8.90%)
         occurrences all number
    274
    272
    Nail discolouration
         subjects affected / exposed
    175 / 2364 (7.40%)
    178 / 2405 (7.40%)
         occurrences all number
    183
    181
    Nail disorder
         subjects affected / exposed
    280 / 2364 (11.84%)
    284 / 2405 (11.81%)
         occurrences all number
    299
    301
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    216 / 2364 (9.14%)
    157 / 2405 (6.53%)
         occurrences all number
    237
    168
    Pruritus
         subjects affected / exposed
    331 / 2364 (14.00%)
    217 / 2405 (9.02%)
         occurrences all number
    399
    272
    Rash
         subjects affected / exposed
    604 / 2364 (25.55%)
    487 / 2405 (20.25%)
         occurrences all number
    782
    634
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    678 / 2364 (28.68%)
    781 / 2405 (32.47%)
         occurrences all number
    895
    1117
    Back pain
         subjects affected / exposed
    207 / 2364 (8.76%)
    237 / 2405 (9.85%)
         occurrences all number
    248
    267
    Bone pain
         subjects affected / exposed
    223 / 2364 (9.43%)
    256 / 2405 (10.64%)
         occurrences all number
    285
    345
    Muscle spasms
         subjects affected / exposed
    217 / 2364 (9.18%)
    123 / 2405 (5.11%)
         occurrences all number
    269
    148
    Musculoskeletal pain
         subjects affected / exposed
    201 / 2364 (8.50%)
    215 / 2405 (8.94%)
         occurrences all number
    241
    256
    Myalgia
         subjects affected / exposed
    613 / 2364 (25.93%)
    708 / 2405 (29.44%)
         occurrences all number
    823
    964
    Pain in extremity
         subjects affected / exposed
    234 / 2364 (9.90%)
    252 / 2405 (10.48%)
         occurrences all number
    274
    311
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    147 / 2364 (6.22%)
    124 / 2405 (5.16%)
         occurrences all number
    160
    130
    Nasopharyngitis
         subjects affected / exposed
    315 / 2364 (13.32%)
    284 / 2405 (11.81%)
         occurrences all number
    473
    414
    Rhinitis
         subjects affected / exposed
    141 / 2364 (5.96%)
    116 / 2405 (4.82%)
         occurrences all number
    167
    130
    Upper respiratory tract infection
         subjects affected / exposed
    184 / 2364 (7.78%)
    173 / 2405 (7.19%)
         occurrences all number
    227
    222
    Urinary tract infection
         subjects affected / exposed
    180 / 2364 (7.61%)
    155 / 2405 (6.44%)
         occurrences all number
    228
    188
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    561 / 2364 (23.73%)
    478 / 2405 (19.88%)
         occurrences all number
    912
    737
    Hypokalaemia
         subjects affected / exposed
    150 / 2364 (6.35%)
    97 / 2405 (4.03%)
         occurrences all number
    192
    112
    Hypomagnesaemia
         subjects affected / exposed
    145 / 2364 (6.13%)
    78 / 2405 (3.24%)
         occurrences all number
    177
    94

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2012
    This amendment was made mainly to adjust for a higher than expected rate of recruitment of node-negative participants. The trial sample size was increased from N=3806 to N=4800 and node-negative participants were no longer permitted to enroll. The recruitment period was adjusted (from 27 to 25 months) and a clause was included to ensure that the primary analysis did not take place until at least 30 months after the last participant enrolled. Additional protocol revisions included following: - The time from randomization to first treatment was increased from 7 weeks to 8 weeks to allow participants more time to enter study. - The number of centers was reduced from 700 to 600. - The number of cycles of 5 fluorouracil, epirubicin and cyclophosphamide (FEC)/5-fluorouracil, doxorubicin and cyclophosphamide (FAC) was made more flexible (3 or 4) to more closely reflect local practice. - Reporting of non-breast second primary malignancies was added, in line with protocol-specified endpoints. - The minimum observation period after administration of pertuzumab was adjusted to align with the current pertuzumab label. - The order of administration of docetaxel, carboplatin and trastuzumab (TCH) was updated in line with current practice, in addition to clarifying the dose and time period of administration. - A range of clarifications were added including to the eligibility criteria (examples of concurrent serious diseases added), the requirements for participants undergoing sentinel lymph node biopsies, the reporting of concomitant medications and prior treatments for breast cancer, the information to be collected at the time of partial withdrawal from the study, and to the timing of assessments and sample collection.
    03 Dec 2013
    This amendment consisted mainly of clarifications, corrections of minor inconsistencies and minor adjustments, as follows: - A 3-day window for the last dose of targeted therapy was added at the end of 52 weeks. - The investigational medicinal product (IMP) terminology was clarified to refer specifically to pertuzumab (‘targeted treatment’ referred to pertuzumab + trastuzumab; ‘study drugs’ referred to pertuzumab + trastuzumab + chemotherapy). - Due to multiple queries from sites, the language associated with the investigators’ choice of adjuvant chemotherapy was revised, and information on excluded anti-cancer agents was added. - Follow-up of adverse events was clarified (until resolution or end of study); also the assessment schedules for participants according to treatments received. Footnotes to the schedule of assessment tables were also added or revised, for example relating to the requirements for yearly mammograms. - Mentions of optional cores from the original tumor block for non-heritable factors were removed.
    02 Feb 2015
    This amendment was made primarily to include details of enhanced measures for reporting of pregnancies that occur during study treatment or within 6 months after completion of pertuzumab treatment. In addition, the following changes were made: - The washout period for trastuzumab was increased to 7 months based on updated half-life data for trastuzumab. - Related warnings (pregnancy exclusion and cardiac toxicity risk) were revised based on the updated trastuzumab washout period. - Endocrine therapy recommendations were revised (to allow endocrine therapy administration as per local practice). - An additional plasma sample at disease recurrence was added. - Various clarifications were made (to sample collection, definitions and reporting requirements).

    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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