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    Clinical Trial Results:
    A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer (MBC)

    Summary
    EudraCT number
    		 2009-017905-13
    Trial protocol
    		 AT   ES   DE   FR   SE   DK   HU   CZ   GB   IT   BE   PT   GR  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    07 Jan 2017
    First version publication date
    07 Jan 2017
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BO22589
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01120184
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, CH, Basel, Switzerland, 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
    16 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Sep 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This randomized, three-arm, multicenter, Phase III study was designed to evaluate the efficacy and safety of trastuzumab emtansine with and without pertuzumab, versus the combination of trastuzumab with taxane therapy, among participants with human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer (LABC) or metastatic breast cancer (MBC) who had not received prior chemotherapy for their metastatic disease.
    Protection of trial subjects
    All investigators were trained according to applicable Sponsor Standard Operating Procedures (SOPs). Roche and the investigators strictly adhered to the stated provisions in these guidelines. This was documented by the investigator’s signature on the protocol agreeing to carry out all of its terms in accordance with the applicable regulations and law and to follow International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 67 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 79
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Bahamas: 6
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Panama: 5
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United States: 131
    Country: Number of subjects enrolled
    Brazil: 88
    Country: Number of subjects enrolled
    Japan: 82
    Country: Number of subjects enrolled
    United Kingdom: 74
    Country: Number of subjects enrolled
    France: 72
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Spain: 43
    Country: Number of subjects enrolled
    Thailand: 39
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 25
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Philippines: 23
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 21
    Country: Number of subjects enrolled
    Peru: 20
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Guatemala: 12
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Malaysia: 10
    Country: Number of subjects enrolled
    New Zealand: 8
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Argentina: 6
    Worldwide total number of subjects
    1095
    EEA total number of subjects
    405
    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)
    912
    From 65 to 84 years
    179
    85 years and over
    4

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 1629 participants were screened, of whom 1095 were randomized. There were 534 participants who failed screening, most often due to non-centrally confirmed HER2 status or abnormal laboratory results.

    Pre-assignment
    Screening details
    		 A total of 1629 participants were screened, of whom 1095 were randomized. There were 534 participants who failed screening, most often due to non-centrally confirmed HER2 status or abnormal laboratory results.

    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
    Blinding implementation details
    The study was considered open-label with respect to trastuzumab and trastuzumab emtansine treatment; however, participants and investigators were blinded with respect to pertuzumab or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab + Taxane
    Arm description
    		 Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab, docetaxel or paclitaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered via IV infusion and dosed depending upon the taxane selected. Participants received either 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg on Day 1 of each subsequent 3-week cycle, or 4 mg/kg on Day 1 of Cycle 1 followed by 2 mg/kg weekly beginning on Day 8 of Cycle 1.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered via IV infusion as 75 or 100 mg/m^2 on Day 1 of each 3-week cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered via IV infusion as 80 mg/m^2 weekly.

    Arm title
    		 Trastuzumab Emtansine + Placebo
    Arm description
    		 Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
    Arm type
    		 Experimental

    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
    Participants received the placebo equivalent to pertuzumab via IV infusion on Day 1 of each 3-week cycle.

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion on Day 1 of each 3-week cycle.

    Arm title
    		 Trastuzumab Emtansine + Pertuzumab
    Arm description
    		 Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered via IV infusion as 840 mg on Day 1 of Cycle 1, followed by 420 mg on Day 1 of each subsequent 3-week cycle.

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion on Day 1 of each 3-week cycle.

    Number of subjects in period 1
    		Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Started
    365
    367
    363
    Treated
    355
    365
    360
    Completed
    196
    213
    209
    Not completed
    169
    154
    154
         Physician decision
    9
    2
    2
         Consent withdrawn by subject
    28
    28
    22
         Death
    123
    116
    115
         Not Specified
    4
    2
    8
         Lost to follow-up
    5
    6
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab + Taxane
    Reporting group description
    		 Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab, docetaxel or paclitaxel were discontinued for toxicity, the other agent could be continued as monotherapy.

    Reporting group title
    Trastuzumab Emtansine + Placebo
    Reporting group description
    		 Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

    Reporting group title
    Trastuzumab Emtansine + Pertuzumab
    Reporting group description
    		 Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

    Reporting group values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab Total
    Number of subjects
    		 365 367 363 1095
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.2 ( 11.3 ) 52.6 ( 11.4 ) 52.2 ( 12 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 362 365 361 1088
        Male
    		 3 2 2 7

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab + Taxane
    Reporting group description
    		 Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab, docetaxel or paclitaxel were discontinued for toxicity, the other agent could be continued as monotherapy.

    Reporting group title
    Trastuzumab Emtansine + Placebo
    Reporting group description
    		 Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

    Reporting group title
    Trastuzumab Emtansine + Pertuzumab
    Reporting group description
    		 Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

    Subject analysis set title
    Trastuzumab + Taxane - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population for this group included all treated participants; however, 2 participants randomized to this group received 3 cycles of trastuzumab emtansine and were excluded for safety analysis. Hence, safety population for this group=353.

    Subject analysis set title
    Trastuzumab Emtansine + Placebo - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population for this group included all treated participants; however, 2 participants randomized to trastuzumab+taxane received 3 cycles of trastuzumab emtansine and were included in this group for safety analysis. Six participants randomized to this group received pertuzumab and were excluded from this group. Hence, safety population for this group=361.

    Subject analysis set title
    Trastuzumab Emtansine + Pertuzumab - Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population for this group included all treated participants; however, 6 participants randomized to trastuzumab emtansine+placebo received pertuzumab and were included in this arm for safety analysis. Hence, safety population for this group=366.

    Primary: Percentage of Participants with Death or Disease Progression According to Independent Review Facility (IRF) Assessment

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    End point title
    		 Percentage of Participants with Death or Disease Progression According to Independent Review Facility (IRF) Assessment [1]
    End point description
    Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population (all participants randomized in the study).
    End point type
    Primary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    Notes
    [1] - 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 data for this endpoint is descriptive and hence, no statistical analysis is provided.
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: percentage of participants
        number (not applicable)
    63.3
    64.3
    59.8
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS) According to IRF Assessment

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    End point title
    		 Progression-Free Survival (PFS) According to IRF Assessment
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression as assessed by IRF or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: months
        median (confidence interval 95%)
    13.7 (12.4 to 14.9)
    14.1 (10.9 to 16.8)
    15.2 (12.5 to 18.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.3125 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.13
    Notes
    [2] - The study was powered for superiority with target hazard ratio (HR) equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was less than (<) 1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00.
    [3] - Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 = 0.1407 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.08
    Notes
    [4] - The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was <1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00.
    [5] - Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent). Formal comparison planned depending on superiority for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane.
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 = 0.3075 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.13
    Notes
    [6] - The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was <1.1765. Superiority was achieved if the upper bound of the 97.5% CI was < 1.00. Formal comparison planned depending on superiority for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane.
    [7] - Test and p-value apply for superiority test. Primary endpoint did not meet superiority of PFS for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane (two-sided significance level 2.5%); thus, tests and p-value are considered descriptive.

    Secondary: Percentage of Participants Who Died Prior to Clinical Cutoff

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    End point title
    		 Percentage of Participants Who Died Prior to Clinical Cutoff
    End point description
    The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: percentage of participants
        number (not applicable)
    33.7
    31.6
    31.7
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at Clinical Cutoff

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    End point title
    		 Overall Survival (OS) at Clinical Cutoff
    End point description
    OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Here, "9999" represents that the value is not applicable because Median duration of OS was not reached due to insufficient followup. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: months
        median (confidence interval 95%)
    9999 (41.1 to 9999)
    9999 (44.7 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.16
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.11

    Secondary: Percentage of Participants with Death or Disease Progression According to Investigator Assessment

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    End point title
    		 Percentage of Participants with Death or Disease Progression According to Investigator Assessment
    End point description
    Tumor assessments were performed by the investigator according to RECIST version 1.1. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: percentage of participants
        number (not applicable)
    72.1
    70.3
    67.5
    No statistical analyses for this end point

    Secondary: PFS According to Investigator Assessment

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    End point title
    		 PFS According to Investigator Assessment
    End point description
    Tumor assessments were performed by the investigator according to RECIST version 1.1. PFS was defined as the time from randomization to progression of disease as assessed by Investigator or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: months
        median (confidence interval 95%)
    12.5 (10.5 to 13.6)
    14.1 (12.2 to 16.7)
    14.8 (12.4 to 17.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.04
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.95

    Secondary: Percentage of Participants Experiencing Treatment Failure

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    End point title
    		 Percentage of Participants Experiencing Treatment Failure
    End point description
    Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. The percentage of participants with treatment failure was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: percentage of participants
        number (not applicable)
    85.8
    82.6
    80.2
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure (TTF)

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    End point title
    		 Time to Treatment Failure (TTF)
    End point description
    Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or participant withdrawal. TTF is the time from randomization to discontinuation of all agents in the respective treatment arm for any reason, including disease progression, treatment toxicity, death from any cause, or patient/physician decision to discontinue study treatment. Median TTF was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: months
        median (confidence interval 95%)
    10.2 (9.2 to 11.8)
    12.1 (9.9 to 13.9)
    11.8 (9.9 to 14.2)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.95
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.97

    Secondary: One-Year Survival Rate

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    End point title
    		 One-Year Survival Rate
    End point description
    The percentage of participants alive at 1 year after randomization was estimated as the one-year survival rate using Kaplan-Meier analysis, and corresponding CIs were computed using Greenwood's estimate of the standard error. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization until 1 year
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: percentage probability of being alive
        number (confidence interval 95%)
    91.4 (88.44 to 94.41)
    92.4 (89.62 to 95.15)
    91.9 (89 to 94.77)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Grade ≥3 Adverse Events

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    End point title
    		 Percentage of Participants with Grade ≥3 Adverse Events
    End point description
    Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Grade 5: Death. Safety Population: All treated participants. Additionally, 2 participants randomized to trastuzumab+taxane received 3 cycles of trastuzumab emtansine and were included in trastuzumab emtansine+placebo arm. 6 participants randomized to trastuzumab emtansine+placebo received pertuzumab and were included in trastuzumab emtansine+pertuzumab arm.
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose
    End point values
    		 Trastuzumab + Taxane - Safety Population Trastuzumab Emtansine + Placebo - Safety Population Trastuzumab Emtansine + Pertuzumab - Safety Population
    Number of subjects analysed
    353
    361
    366
    Units: percentage of participants
        number (not applicable)
    54.1
    45.4
    46.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died at 2 Years

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    End point title
    		 Percentage of Participants Who Died at 2 Years
    End point description
    Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization until 2 years
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: percentage of participants
        number (not applicable)
    20.3
    20.2
    19.6
    No statistical analyses for this end point

    Secondary: Overall Survival Truncated at 2 Years

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    End point title
    		 Overall Survival Truncated at 2 Years
    End point description
    Overall Survival truncated at 2 years was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at 2 years had been censored at 2 years. Median duration of overall survival truncated at 2 years was estimated using Kaplan-Meier analyses, and corresponding CIs were computed using the Brookmeyer-Crowley method. Here, "9999" represents that data was not applicable because median was not reached at 2 years as most of the participants were alive at that time point. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization until 2 years
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.31
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.29
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.46

    Secondary: Percentage of Participants with Grade 5 Adverse Events

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    End point title
    		 Percentage of Participants with Grade 5 Adverse Events
    End point description
    Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death.Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose
    End point values
    		 Trastuzumab + Taxane - Safety Population Trastuzumab Emtansine + Placebo - Safety Population Trastuzumab Emtansine + Pertuzumab - Safety Population
    Number of subjects analysed
    353
    361
    366
    Units: percentage of participants
        number (not applicable)
    1.7
    1.1
    1.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Grade 3-4 Laboratory Parameters

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    End point title
    		 Percentage of Participants with Grade 3-4 Laboratory Parameters
    End point description
    Laboratory results were graded according to NCI CTCAE version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Analysis was performed on safety population. Number of participants analyzed=participants with available data for the outcome.
    End point type
    Secondary
    End point timeframe
    Day 1, 8, and 15 of Cycle 1–3 and on Day 1 of each subsequent cycle up to 50 months from randomization until clinical cutoff of 16-Sept-2014
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    352
    361
    363
    Units: percentage of participants
    number (not applicable)
        Hemoglobin-Low: Grade 3
    4.3
    5.8
    6.9
        Neutrophils-Low: Grade 3
    20.2
    5.5
    5
        Neutrophils-Low: Grade 4
    43.8
    1.9
    0.8
        Platelets-Low: Grade 3
    0.9
    12.7
    12.9
        Platelets-Low: Grade 4
    0.3
    2.8
    2.5
        Alkaline Phosphate-High: Grade 3
    1.1
    3.9
    3
        Alanine Transaminase-High: Grade 3
    3.4
    9.1
    8
        Alanine Transaminase-High: Grade 4
    0
    0.3
    0.6
        Aspartate Aminotransferase-High: Grade 3
    1.1
    11.9
    6.9
        Aspartate Aminotransferase-High: Grade 4
    0
    0.3
    0.3
        Creatinine-High: Grade 3
    0.9
    0.3
    1.1
        Creatinine-High: Grade 4
    0
    0
    0.3
        Potassium-Low: Grade 3
    4.3
    4.7
    5.2
        Potassium-Low: Grade 4
    0.6
    1.7
    0.6
        Total Bilirubin-High: Grade 3
    0.3
    0.3
    0.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Decline of ≥2 points from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

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    End point title
    		 Percentage of Participants with Decline of ≥2 points from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
    End point description
    The ECOG performance status is a scale used to quantify cancer participants' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all predisease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, < 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, > 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months)
    End point values
    		 Trastuzumab + Taxane - Safety Population Trastuzumab Emtansine + Placebo - Safety Population Trastuzumab Emtansine + Pertuzumab - Safety Population
    Number of subjects analysed
    353
    361
    366
    Units: percentage of participants
        number (not applicable)
    7.6
    6.1
    7.9
    No statistical analyses for this end point

    Secondary: Hospitalization Days

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    End point title
    		 Hospitalization Days
    End point description
    Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Reported values represent number of days admitted per participants. Analysis was performed on safety population .Number of participants analyzed=participants with hospitalization and data available for calculation of the parameter.
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
    End point values
    		 Trastuzumab + Taxane - Safety Population Trastuzumab Emtansine + Placebo - Safety Population Trastuzumab Emtansine + Pertuzumab - Safety Population
    Number of subjects analysed
    353
    361
    366
    Units: days
        median (full range (min-max))
    6 (1 to 50)
    5 (1 to 117)
    8 (1 to 381)
    No statistical analyses for this end point

    Secondary: Percentage of participants with Hospitalization

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    End point title
    		 Percentage of participants with Hospitalization
    End point description
    Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
    End point values
    		 Trastuzumab + Taxane - Safety Population Trastuzumab Emtansine + Placebo - Safety Population Trastuzumab Emtansine + Pertuzumab - Safety Population
    Number of subjects analysed
    353
    361
    366
    Units: percentage of participants
        number (confidence interval 95%)
    21.8 (17.62 to 26.36)
    20.2 (16.2 to 24.71)
    22.1 (18.03 to 26.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Objective Response According to IRF Assessment

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    End point title
    		 Percentage of Participants with Objective Response According to IRF Assessment
    End point description
    Objective response was defined as having complete response (CR) or partial response (PR), assessed according to RECIST version 1.1, using radiographic images submitted to IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR: disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR: a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the objective response rate [ORR]) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method. ITT population. Only participants with measurable disease by IRF at Baseline were included.
    End point type
    Secondary
    End point timeframe
    Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    287
    303
    299
    Units: percentage of participants
        number (confidence interval 95%)
    67.9 (62.26 to 73.31)
    59.7 (54.07 to 65.3)
    64.2 (58.62 to 69.65)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    590
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    -8.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.9
         upper limit
    		 -0.5
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.4
         upper limit
    		 3.9
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 12.2

    Secondary: Percentage of Participants with Objective Response According to Investigator Assessment

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    End point title
    		 Percentage of Participants with Objective Response According to Investigator Assessment
    End point description
    Objective response was defined as having CR or PR, assessed according to RECIST version 1.1, by investigator. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method. Only participants with measurable disease by Investigator at Baseline were included in the analysis. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    293
    314
    311
    Units: percentage of participants
        number (confidence interval 95%)
    69.3 (63.74 to 74.52)
    64.6 (59.12 to 69.87)
    67.5 (62.17 to 72.68)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    607
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 2.8
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    604
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 5.7
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 10.3

    Secondary: Duration of Response According to IRF Assessment

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    End point title
    		 Duration of Response According to IRF Assessment
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Duration of response was defined as the time from confirmed PR or CR to first documented disease progression or death from any cause. CR was defined as the disappearance of all target lesions and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. Median duration of response was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population. Only participants achieving CR or PR were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    195
    181
    192
    Units: months
        median (confidence interval 95%)
    12.5 (10.5 to 16.6)
    20.7 (14.8 to 25)
    21.2 (15.8 to 29.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.84
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.85

    Secondary: Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment

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    End point title
    		 Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient (20%) increase to qualify for disease progression. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR, PR, or SD was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: percentage of participants
        number (not applicable)
    Notes
    [8] - This outcome was removed because it was redundant to another prespecified secondary endpoint.
    [9] - This outcome was removed because it was redundant to another prespecified secondary endpoint.
    [10] - This outcome was removed because it was redundant to another prespecified secondary endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score

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    End point title
    		 Percentage of Participants Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score
    End point description
    The FACT-Taxane is a self-reported instrument which measures health-related quality of life (HRQOL) of participants receiving taxane-containing chemotherapy. FACT-TaxS consists of 16 items (11 neurotoxicity-related questions and 5 additional questions assessing arthralgia, myalgia, and skin discoloration). Items are rated from 0 (not at all) to 4 (very much) and total score is inversely derived. Scores may range from 0 to 64, with higher scores indicating fewer/no symptoms. A minimally clinically important difference in treatment-related symptoms was defined as ≥5% decrease (ie, 3.2 points) in FACT-TaxS score from Baseline. Percentage of participants with treatment-related symptoms was calculated using following formula: [participants meeting above threshold divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method. Protocol Amendment C Subpopulation: All randomized participants who entered after Protocol Amendment C.
    End point type
    Secondary
    End point timeframe
    Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    173
    171
    154
    Units: percentage of participants
        number (confidence interval 95%)
    93.1 (88.48 to 96.06)
    60.8 (53.39 to 67.93)
    68.8 (61.32 to 75.92)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs Tratuzumab + Taxane
    Point estimate
    -32.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40
         upper limit
    		 -24
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs Tratuzumab + Taxane
    Point estimate
    -24.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32
         upper limit
    		 -16
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs TDM-1+Placebo
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 18.4

    Secondary: Percentage of Participants Reporting Nausea According to Item GP2 of The FACT Colorectal Cancel (FACT-C) Module

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    End point title
    		 Percentage of Participants Reporting Nausea According to Item GP2 of The FACT Colorectal Cancel (FACT-C) Module
    End point description
    The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with nausea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100. Protocol Amendment C Subpopulation. Only participants with a FACT-C score at the designated visit (n) were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    173
    171
    154
    Units: percentage of participants
    number (not applicable)
        Nausea, Baseline (n=166,166,150)
    22.3
    14.5
    21.3
        Nausea, Cycle 1 Day 8 (n=121,114,95)
    38
    36
    52.6
        Nausea, Cycle 2 Day 1 (n=147,151,138)
    27.2
    20.5
    36.2
        Nausea, Cycle 2 Day 8 (n=122,121,105)
    35.2
    28.1
    45.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Reporting Diarrhea According to Single Item C5 of The FACT-C Module

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    End point title
    		 Percentage of Participants Reporting Diarrhea According to Single Item C5 of The FACT-C Module
    End point description
    The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of participants with diarrhea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100. Protocol Amendment C Subpopulation. Only participants with a FACT-C score at the designated visit (n) were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    173
    171
    154
    Units: percentage of participants
    number (not applicable)
        Diarrhea, Baseline (n=173,170,153)
    15
    7.6
    11.8
        Diarrhea, Cycle 1 Day 8 (n=124,117,98)
    34.7
    17.9
    34.7
        Diarrhea, Cycle 2 Day 1 (n=161,160,144)
    24.2
    11.3
    39.6
        Diarrhea, Cycle 2 Day 8 (n=125,123,107)
    34.4
    8.1
    41.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score

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    End point title
    		 Percentage of Participants with a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score
    End point description
    The FACT-B is self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. The percentage of participants with deterioration was calculated as [number of participants meeting above threshold divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population. Number of participants analyzed=participants with baseline and at least 1 post baseline FACT-B TOI-PFB score.
    End point type
    Secondary
    End point timeframe
    Up to 39 months from randomization until progression or clinical cutoff of 16-Sept-2014 (Pre amendment C: every 9 weeks for 1st 81 weeks, every 12 weeks thereafter; post amendment C: 1st day of every cycle for first 8 cycles, every other cycle thereafter)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    327
    352
    338
    Units: percentage of participants
        number (not applicable)
    61.8
    50.9
    50.6
    No statistical analyses for this end point

    Secondary: Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score

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    End point title
    		 Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score
    End point description
    The FACT-B is a self-reported instrument which measures HRQOL of participants with breast cancer. It consists of 5 subscales including PWB, SWB, EWB, FWB, and BCS. The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. Time to deterioration was defined as the time from Baseline until the first decrease in FACT-B TOI-PFB score. Median time to deterioration was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT Population. Number of participants analyzed=participants with baseline and at least one post baseline FACT-B TOI-PFB score.
    End point type
    Secondary
    End point timeframe
    Up to 39 months from randomization until progression or clinical cutoff of 16-Sept-2014 (Pre amendment C: every 9 weeks for 1st 81 weeks, every 12 weeks thereafter; post amendment C: 1st day of every cycle for first 8 cycles, every other cycle thereafter)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    327
    352
    338
    Units: months
        median (confidence interval 95%)
    3.6 (3 to 4.4)
    7.7 (6.2 to 11.9)
    9 (5.1 to 14.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.86
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
    Comparison groups
    Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.84

    Secondary: Change from Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score

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    End point title
    		 Change from Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score
    End point description
    The RSCL is a self-reported instrument which consists of 4 domains including physical symptom distress, psychological distress, activity level, and overall global life quality. Only the activity level scale was collected and assessed. Scores may range from 0 to 100, with higher scores indicating increased burden of disease. Mean RSCL activity scale score changes were calculated as [mean score at the assessment visit minus mean score at Baseline]. The higher the score, the higher the level of impairment or burden. Analysis was performed on ITT Population. Here, 'n' signifies the number of participants with available data at baseline and Cycle 7 (Week 18).
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 7 (Week 18)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    365
    367
    363
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Baseline (n=344,355,344)
    85 (82.9 to 87.2)
    85.5 (83.3 to 87.8)
    85.7 (83.5 to 87.8)
        Change From Baseline at Cycle 7 (n=261,252,261)
    -1.6 (-4.2 to 1)
    2.3 (0.4 to 4.2)
    -0.2 (-2.1 to 1.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score

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    End point title
    		 Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
    End point description
    The WPAI is patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate number of hours missed from work due to reasons related and unrelated to their health problems, as well as total number of hours actually worked in preceding 7-day period. Percentage of participants reporting that they were employed (working for pay) was assessed at baseline along with Absenteeism (work time missed), Presenteeism (impairment at work/reduced on-job effectiveness), Work productivity loss (overall work impairment/absenteeism plus presenteeism), and Activity Impairment. Reported changes represent change from baseline at Cycle 7. The score range for scales of the WPAI is 0 (no effect) to 100% (max effect). Number of participants analysed=participants from ITT population who were employed at baseline. Here, 'n' signifies the number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 7 (Week 18)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    67
    64
    67
    Units: percent of work
    arithmetic mean (confidence interval 95%)
        % Work Time Missed at Baseline (n=66,63,67)
    15.3 (9.2 to 21.4)
    9.5 (4.2 to 14.8)
    13.6 (7.7 to 19.6)
        Change in % Work Time Missed (n=35,33,36)
    0.4 (-7.3 to 8.2)
    0 (-4.5 to 4.5)
    -4.3 (-13 to 4.6)
        % Impairment While Working at Baseline(n=67,64,67)
    20 (14.1 to 25.9)
    15.3 (9.5 to 21.1)
    19.9 (13.6 to 26.1)
        Change in % Impairment While Working (n=34,32,35)
    8.8 (2 to 15.6)
    -0.3 (-11 to 10.5)
    -2.7 (-11 to 5.2)
        % Overall Work Impairment at Baseline (n=65,62,66)
    28.5 (20.7 to 36.2)
    21.2 (13.8 to 28.7)
    28.1 (20.3 to 35.9)
        Change in % Overall Work Impairment (n=34,31,35)
    9.1 (-0.4 to 18.6)
    -1.1 (-13 to 11)
    -4.6 (-14 to 5)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score

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    End point title
    		 Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score
    End point description
    The WPAI is patient-reported measure which assesses effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks participants to estimate number of hours missed from work due to reasons related and unrelated to their health problems, as well as total number of hours actually worked in preceding 7-day period. Percentage of participants reporting that they were employed (working for pay) was assessed at baseline along with Absenteeism (work time missed), Presenteeism (impairment at work/reduced on-the-job effectiveness), Work productivity loss (overall work mpairment/absenteeism plus presenteeism), and Activity Impairment. Reported changes represent change from baseline at Cycle 7. The score range for the scales of WPAI is 0 (no effect) to 100% (max effect). Number of participants analysed=participants from ITT population who were employed at baseline. Here, 'n' signifies the number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 7 (Week 18)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    312
    334
    321
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        % Activity Impairment at Baseline (n=312,334,321)
    32.9 (29.6 to 36.3)
    33.6 (30.2 to 37)
    32.7 (29.5 to 36)
        Change in % Activity Impairment (n=227,222,234)
    4.5 (0.2 to 8.7)
    -5.3 (-9.5 to -1.1)
    -3.7 (-7.2 to -0.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Best Overall Response of CR or PR According to IRF Assessment Among Those with High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels

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    End point title
    		 Percentage of Participants with a Best Overall Response of CR or PR According to IRF Assessment Among Those with High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. ITT Population (High HER2 mRNA Subpopulation): All randomized participants with above the median HER2 mRNA expression (value greater than [>] 59.71). Only participants with measurable disease at Baseline were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    132
    136
    147
    Units: percentage of participants
        number (not applicable)
    75
    66.9
    63.9
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.15

    Secondary: Percentage of Participants with a Best Overall Response of CR or PR According to IRF Assessment Among Those with Low HER2 mRNA Levels

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    End point title
    		 Percentage of Participants with a Best Overall Response of CR or PR According to IRF Assessment Among Those with Low HER2 mRNA Levels
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. ITT Population (Low HER2 mRNA Subpopulation): All randomized participants with below-the-median HER2 mRNA expression (value less than or equal to [≤] 59.71). Only participants with measurable disease at Baseline were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    126
    147
    127
    Units: percentage of participants
        number (not applicable)
    61.9
    51.7
    66.1
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.07

    Secondary: Percentage of Participants with Death or Disease Progression According to IRF Assessment Among Those with High HER2 mRNA Levels

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    End point title
    		 Percentage of Participants with Death or Disease Progression According to IRF Assessment Among Those with High HER2 mRNA Levels
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population (High HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    160
    165
    173
    Units: percentage of participants
        number (not applicable)
    59.4
    57.6
    56.1
    No statistical analyses for this end point

    Secondary: PFS According to IRF Assessment Among Those with High HER2 mRNA Levels

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    End point title
    		 PFS According to IRF Assessment Among Those with High HER2 mRNA Levels
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis. Analysis was performed on ITT Population (High HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    160
    165
    173
    Units: months
        median (full range (min-max))
    15.9 (0.1 to 46.4)
    18.6 (0.1 to 46)
    18.7 (0.1 to 48.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.25

    Secondary: Percentage of Participants with Death or Disease Progression According to IRF Assessment Among Those with Low HER2 mRNA Levels

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    End point title
    		 Percentage of Participants with Death or Disease Progression According to IRF Assessment Among Those with Low HER2 mRNA Levels
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population (Low HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    170
    174
    157
    Units: percentage of participants
        number (not applicable)
    66.5
    70.1
    62.4
    No statistical analyses for this end point

    Secondary: PFS According to IRF Assessment Among Those with Low HER2 mRNA Levels

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    End point title
    		 PFS According to IRF Assessment Among Those with Low HER2 mRNA Levels
    End point description
    Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis. Analysis was performed on ITT Population (Low HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    170
    174
    157
    Units: months
        median (full range (min-max))
    12.4 (0.1 to 47.3)
    10.2 (0.1 to 43.6)
    14.5 (0.1 to 40.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.34

    Secondary: Percentage of Participants Who Died Prior to Clinical Cutoff Among Those with High HER2 mRNA Levels

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    End point title
    		 Percentage of Participants Who Died Prior to Clinical Cutoff Among Those with High HER2 mRNA Levels
    End point description
    The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population (High HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    160
    165
    173
    Units: percentage of participants
        number (not applicable)
    28.1
    27.9
    29.5
    No statistical analyses for this end point

    Secondary: OS at Clinical Cutoff Among Those with High HER2 mRNA Levels

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    End point title
    		 OS at Clinical Cutoff Among Those with High HER2 mRNA Levels
    End point description
    OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Here, 9.99 represents data not applicable because median duration of OS was not reached due to insufficient follow up. Confidence interval values are censored values. Analysis was performed on ITT Population (High HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    160
    165
    173
    Units: months
        median (full range (min-max))
    9.99 (0.1 to 48.4)
    9.99 (0.6 to 48.1)
    9.99 (0.1 to 48.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.51

    Secondary: Percentage of Participants Who Died Prior to Clinical Cutoff Among Those with Low HER2 mRNA Levels

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    End point title
    		 Percentage of Participants Who Died Prior to Clinical Cutoff Among Those with Low HER2 mRNA Levels
    End point description
    The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population (Low HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    170
    174
    157
    Units: percentage of participants
        number (not applicable)
    37.6
    33.9
    30.6
    No statistical analyses for this end point

    Secondary: OS at Clinical Cutoff Among Those with Low HER2 mRNA Levels

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    End point title
    		 OS at Clinical Cutoff Among Those with Low HER2 mRNA Levels
    End point description
    OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Here, "9.99" represents that data is not applicable because median duration of OS was not reached due to insufficient followup. Reported upper bound of confidence interval for "Trastuzumab Emtansine + Placebo" and confidence interval values for "Trastuzumab + Taxane" and "Trastuzumab Emtansine + Pertuzumab" are censored values. Analysis was performed on ITT Population (Low HER2 mRNA Subpopulation).
    End point type
    Secondary
    End point timeframe
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
    End point values
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Pertuzumab
    Number of subjects analysed
    170
    174
    157
    Units: months
        median (full range (min-max))
    41.9 (0.1 to 48)
    9.99 (0.3 to 49.8)
    9.99 (0.1 to 47.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.27

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose)
    Adverse event reporting additional description
    Safety Population: All randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Trastuzumab + Taxane
    Reporting group description
    		 Participants received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.

    Reporting group title
    Trastuzumab Emtansine + Pertuzumab
    Reporting group description
    		 Participants received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

    Reporting group title
    Trastuzumab Emtansine + Placebo
    Reporting group description
    		 Participants received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.

    Serious adverse events
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Pertuzumab Trastuzumab Emtansine + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 353 (22.66%)
    85 / 366 (23.22%)
    77 / 361 (21.33%)
         number of deaths (all causes)
    123
    116
    114
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 353 (0.57%)
    4 / 366 (1.09%)
    5 / 361 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 353 (0.85%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Device breakage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Pain
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site haematoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 353 (0.00%)
    5 / 366 (1.37%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    2 / 353 (0.57%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial hypertrophy
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    3 / 353 (0.85%)
    3 / 366 (0.82%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 353 (1.13%)
    0 / 366 (0.00%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 366 (0.27%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 353 (0.00%)
    3 / 366 (0.82%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alveolitis allergic
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 353 (0.28%)
    11 / 366 (3.01%)
    6 / 361 (1.66%)
         occurrences causally related to treatment / all
    1 / 1
    11 / 11
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 366 (0.82%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation retinopathy
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial injury
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial injury ABC
    Additional description: ABCD
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    4 / 366 (1.09%)
    4 / 361 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    14 / 353 (3.97%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    15 / 15
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 353 (1.70%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercoagulation
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ocular hypertension
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 353 (1.13%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 366 (0.82%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic artery aneurysm
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peau D’orange
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 366 (0.27%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 353 (0.85%)
    3 / 366 (0.82%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Cellulitis
         subjects affected / exposed
    3 / 353 (0.85%)
    1 / 366 (0.27%)
    3 / 361 (0.83%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 366 (0.82%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 366 (0.27%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 353 (0.85%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 366 (0.55%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chorioretinitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    1 / 361 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 366 (0.27%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 366 (0.00%)
    2 / 361 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 366 (0.00%)
    0 / 361 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab + Taxane Trastuzumab Emtansine + Pertuzumab Trastuzumab Emtansine + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    342 / 353 (96.88%)
    350 / 366 (95.63%)
    351 / 361 (97.23%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 353 (5.67%)
    43 / 366 (11.75%)
    36 / 361 (9.97%)
         occurrences all number
    28
    66
    75
    Hot flush
         subjects affected / exposed
    26 / 353 (7.37%)
    12 / 366 (3.28%)
    15 / 361 (4.16%)
         occurrences all number
    31
    18
    21
    Lymphoedema
         subjects affected / exposed
    25 / 353 (7.08%)
    7 / 366 (1.91%)
    7 / 361 (1.94%)
         occurrences all number
    33
    8
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    127 / 353 (35.98%)
    125 / 366 (34.15%)
    117 / 361 (32.41%)
         occurrences all number
    241
    258
    222
    Pyrexia
         subjects affected / exposed
    57 / 353 (16.15%)
    117 / 366 (31.97%)
    96 / 361 (26.59%)
         occurrences all number
    85
    176
    155
    Asthenia
         subjects affected / exposed
    57 / 353 (16.15%)
    63 / 366 (17.21%)
    61 / 361 (16.90%)
         occurrences all number
    163
    202
    190
    Chills
         subjects affected / exposed
    14 / 353 (3.97%)
    98 / 366 (26.78%)
    56 / 361 (15.51%)
         occurrences all number
    15
    127
    70
    Oedema peripheral
         subjects affected / exposed
    98 / 353 (27.76%)
    31 / 366 (8.47%)
    34 / 361 (9.42%)
         occurrences all number
    176
    38
    48
    Mucosal inflammation
         subjects affected / exposed
    45 / 353 (12.75%)
    35 / 366 (9.56%)
    33 / 361 (9.14%)
         occurrences all number
    62
    54
    55
    Influenza like illness
         subjects affected / exposed
    16 / 353 (4.53%)
    31 / 366 (8.47%)
    29 / 361 (8.03%)
         occurrences all number
    30
    71
    43
    Non-cardiac chest pain
         subjects affected / exposed
    23 / 353 (6.52%)
    26 / 366 (7.10%)
    25 / 361 (6.93%)
         occurrences all number
    27
    34
    36
    Pain
         subjects affected / exposed
    28 / 353 (7.93%)
    19 / 366 (5.19%)
    25 / 361 (6.93%)
         occurrences all number
    37
    24
    28
    Oedema
         subjects affected / exposed
    31 / 353 (8.78%)
    3 / 366 (0.82%)
    9 / 361 (2.49%)
         occurrences all number
    51
    3
    9
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    18 / 353 (5.10%)
    15 / 366 (4.10%)
    13 / 361 (3.60%)
         occurrences all number
    26
    18
    13
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    52 / 353 (14.73%)
    125 / 366 (34.15%)
    112 / 361 (31.02%)
         occurrences all number
    82
    282
    233
    Cough
         subjects affected / exposed
    72 / 353 (20.40%)
    74 / 366 (20.22%)
    70 / 361 (19.39%)
         occurrences all number
    122
    103
    100
    Dyspnoea
         subjects affected / exposed
    54 / 353 (15.30%)
    49 / 366 (13.39%)
    41 / 361 (11.36%)
         occurrences all number
    85
    69
    71
    Oropharyngeal pain
         subjects affected / exposed
    28 / 353 (7.93%)
    28 / 366 (7.65%)
    29 / 361 (8.03%)
         occurrences all number
    35
    39
    31
    Rhinorrhoea
         subjects affected / exposed
    25 / 353 (7.08%)
    31 / 366 (8.47%)
    23 / 361 (6.37%)
         occurrences all number
    37
    35
    28
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    51 / 353 (14.45%)
    50 / 366 (13.66%)
    48 / 361 (13.30%)
         occurrences all number
    61
    70
    68
    Anxiety
         subjects affected / exposed
    22 / 353 (6.23%)
    33 / 366 (9.02%)
    25 / 361 (6.93%)
         occurrences all number
    39
    34
    30
    Depression
         subjects affected / exposed
    17 / 353 (4.82%)
    20 / 366 (5.46%)
    32 / 361 (8.86%)
         occurrences all number
    18
    23
    40
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 353 (2.27%)
    26 / 366 (7.10%)
    55 / 361 (15.24%)
         occurrences all number
    10
    47
    80
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 353 (2.83%)
    33 / 366 (9.02%)
    40 / 361 (11.08%)
         occurrences all number
    12
    55
    66
    Weight decreased
         subjects affected / exposed
    7 / 353 (1.98%)
    29 / 366 (7.92%)
    22 / 361 (6.09%)
         occurrences all number
    10
    39
    40
    Ejection fraction decreased
         subjects affected / exposed
    31 / 353 (8.78%)
    14 / 366 (3.83%)
    8 / 361 (2.22%)
         occurrences all number
    36
    15
    9
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 353 (0.28%)
    17 / 366 (4.64%)
    27 / 361 (7.48%)
         occurrences all number
    1
    23
    34
    Nervous system disorders
    Headache
         subjects affected / exposed
    78 / 353 (22.10%)
    118 / 366 (32.24%)
    116 / 361 (32.13%)
         occurrences all number
    150
    241
    252
    Neuropathy peripheral
         subjects affected / exposed
    99 / 353 (28.05%)
    65 / 366 (17.76%)
    48 / 361 (13.30%)
         occurrences all number
    169
    120
    77
    Peripheral sensory neuropathy
         subjects affected / exposed
    70 / 353 (19.83%)
    44 / 366 (12.02%)
    47 / 361 (13.02%)
         occurrences all number
    123
    70
    66
    Dysgeusia
         subjects affected / exposed
    54 / 353 (15.30%)
    50 / 366 (13.66%)
    29 / 361 (8.03%)
         occurrences all number
    67
    81
    41
    Paraesthesia
         subjects affected / exposed
    39 / 353 (11.05%)
    40 / 366 (10.93%)
    30 / 361 (8.31%)
         occurrences all number
    53
    68
    50
    Dizziness
         subjects affected / exposed
    33 / 353 (9.35%)
    36 / 366 (9.84%)
    36 / 361 (9.97%)
         occurrences all number
    46
    74
    53
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    75 / 353 (21.25%)
    32 / 366 (8.74%)
    41 / 361 (11.36%)
         occurrences all number
    167
    122
    169
    Anaemia
         subjects affected / exposed
    38 / 353 (10.76%)
    55 / 366 (15.03%)
    42 / 361 (11.63%)
         occurrences all number
    60
    111
    63
    Thrombocytopenia
         subjects affected / exposed
    0 / 353 (0.00%)
    53 / 366 (14.48%)
    49 / 361 (13.57%)
         occurrences all number
    0
    162
    139
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    48 / 353 (13.60%)
    19 / 366 (5.19%)
    13 / 361 (3.60%)
         occurrences all number
    58
    22
    18
    Dry eye
         subjects affected / exposed
    13 / 353 (3.68%)
    25 / 366 (6.83%)
    24 / 361 (6.65%)
         occurrences all number
    14
    29
    25
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    172 / 353 (48.73%)
    176 / 366 (48.09%)
    91 / 361 (25.21%)
         occurrences all number
    456
    527
    148
    Nausea
         subjects affected / exposed
    131 / 353 (37.11%)
    191 / 366 (52.19%)
    170 / 361 (47.09%)
         occurrences all number
    300
    579
    484
    Vomiting
         subjects affected / exposed
    67 / 353 (18.98%)
    110 / 366 (30.05%)
    78 / 361 (21.61%)
         occurrences all number
    140
    212
    126
    Constipation
         subjects affected / exposed
    72 / 353 (20.40%)
    71 / 366 (19.40%)
    80 / 361 (22.16%)
         occurrences all number
    119
    128
    139
    Stomatitis
         subjects affected / exposed
    57 / 353 (16.15%)
    40 / 366 (10.93%)
    36 / 361 (9.97%)
         occurrences all number
    76
    60
    50
    Dyspepsia
         subjects affected / exposed
    38 / 353 (10.76%)
    46 / 366 (12.57%)
    35 / 361 (9.70%)
         occurrences all number
    48
    88
    54
    Abdominal pain upper
         subjects affected / exposed
    30 / 353 (8.50%)
    45 / 366 (12.30%)
    38 / 361 (10.53%)
         occurrences all number
    49
    60
    60
    Dry mouth
         subjects affected / exposed
    13 / 353 (3.68%)
    48 / 366 (13.11%)
    52 / 361 (14.40%)
         occurrences all number
    20
    55
    72
    Abdominal pain
         subjects affected / exposed
    30 / 353 (8.50%)
    40 / 366 (10.93%)
    33 / 361 (9.14%)
         occurrences all number
    41
    64
    48
    Gingival bleeding
         subjects affected / exposed
    4 / 353 (1.13%)
    25 / 366 (6.83%)
    31 / 361 (8.59%)
         occurrences all number
    5
    38
    49
    Haemorrhoids
         subjects affected / exposed
    9 / 353 (2.55%)
    21 / 366 (5.74%)
    11 / 361 (3.05%)
         occurrences all number
    9
    37
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    211 / 353 (59.77%)
    33 / 366 (9.02%)
    24 / 361 (6.65%)
         occurrences all number
    249
    35
    25
    Rash
         subjects affected / exposed
    86 / 353 (24.36%)
    86 / 366 (23.50%)
    62 / 361 (17.17%)
         occurrences all number
    146
    134
    105
    Pruritus
         subjects affected / exposed
    32 / 353 (9.07%)
    51 / 366 (13.93%)
    26 / 361 (7.20%)
         occurrences all number
    40
    77
    42
    Nail disorder
         subjects affected / exposed
    54 / 353 (15.30%)
    22 / 366 (6.01%)
    18 / 361 (4.99%)
         occurrences all number
    67
    25
    20
    Dry skin
         subjects affected / exposed
    23 / 353 (6.52%)
    28 / 366 (7.65%)
    21 / 361 (5.82%)
         occurrences all number
    28
    30
    22
    Erythema
         subjects affected / exposed
    24 / 353 (6.80%)
    19 / 366 (5.19%)
    14 / 361 (3.88%)
         occurrences all number
    37
    26
    14
    Dermatitis acneiform
         subjects affected / exposed
    5 / 353 (1.42%)
    27 / 366 (7.38%)
    15 / 361 (4.16%)
         occurrences all number
    5
    41
    15
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    26 / 353 (7.37%)
    10 / 366 (2.73%)
    6 / 361 (1.66%)
         occurrences all number
    29
    13
    7
    Nail discolouration
         subjects affected / exposed
    24 / 353 (6.80%)
    2 / 366 (0.55%)
    5 / 361 (1.39%)
         occurrences all number
    24
    2
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    87 / 353 (24.65%)
    68 / 366 (18.58%)
    79 / 361 (21.88%)
         occurrences all number
    136
    93
    121
    Myalgia
         subjects affected / exposed
    82 / 353 (23.23%)
    62 / 366 (16.94%)
    64 / 361 (17.73%)
         occurrences all number
    158
    113
    147
    Back pain
         subjects affected / exposed
    44 / 353 (12.46%)
    58 / 366 (15.85%)
    54 / 361 (14.96%)
         occurrences all number
    62
    79
    69
    Pain in extremity
         subjects affected / exposed
    44 / 353 (12.46%)
    51 / 366 (13.93%)
    50 / 361 (13.85%)
         occurrences all number
    56
    73
    73
    Muscle spasms
         subjects affected / exposed
    13 / 353 (3.68%)
    61 / 366 (16.67%)
    25 / 361 (6.93%)
         occurrences all number
    18
    91
    33
    Musculoskeletal pain
         subjects affected / exposed
    20 / 353 (5.67%)
    35 / 366 (9.56%)
    29 / 361 (8.03%)
         occurrences all number
    26
    44
    37
    Bone pain
         subjects affected / exposed
    32 / 353 (9.07%)
    28 / 366 (7.65%)
    17 / 361 (4.71%)
         occurrences all number
    49
    66
    21
    Musculoskeletal chest pain
         subjects affected / exposed
    16 / 353 (4.53%)
    19 / 366 (5.19%)
    13 / 361 (3.60%)
         occurrences all number
    21
    19
    16
    Neck pain
         subjects affected / exposed
    12 / 353 (3.40%)
    23 / 366 (6.28%)
    11 / 361 (3.05%)
         occurrences all number
    12
    29
    12
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    53 / 353 (15.01%)
    66 / 366 (18.03%)
    45 / 361 (12.47%)
         occurrences all number
    92
    129
    70
    Nasopharyngitis
         subjects affected / exposed
    47 / 353 (13.31%)
    59 / 366 (16.12%)
    50 / 361 (13.85%)
         occurrences all number
    81
    113
    70
    Urinary tract infection
         subjects affected / exposed
    26 / 353 (7.37%)
    41 / 366 (11.20%)
    28 / 361 (7.76%)
         occurrences all number
    35
    62
    46
    Rhinitis
         subjects affected / exposed
    17 / 353 (4.82%)
    21 / 366 (5.74%)
    22 / 361 (6.09%)
         occurrences all number
    21
    25
    24
    Influenza
         subjects affected / exposed
    12 / 353 (3.40%)
    24 / 366 (6.56%)
    22 / 361 (6.09%)
         occurrences all number
    16
    35
    24
    Paronychia
         subjects affected / exposed
    22 / 353 (6.23%)
    29 / 366 (7.92%)
    7 / 361 (1.94%)
         occurrences all number
    30
    53
    10
    Pharyngitis
         subjects affected / exposed
    16 / 353 (4.53%)
    19 / 366 (5.19%)
    20 / 361 (5.54%)
         occurrences all number
    17
    20
    24
    Conjunctivitis
         subjects affected / exposed
    21 / 353 (5.95%)
    15 / 366 (4.10%)
    13 / 361 (3.60%)
         occurrences all number
    25
    18
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    75 / 353 (21.25%)
    80 / 366 (21.86%)
    82 / 361 (22.71%)
         occurrences all number
    128
    149
    143
    Hypokalaemia
         subjects affected / exposed
    15 / 353 (4.25%)
    28 / 366 (7.65%)
    17 / 361 (4.71%)
         occurrences all number
    18
    38
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2011
    Updates to the protocol included truncation of OS at 2 years as a secondary endpoint, addition of several quality of life assessments including FACT instruments, changes in the assessment schedule, clarification of the study population and eligibility criteria, and addition of treatment guidelines for cases of study drug discontinuation.
    11 Oct 2011
    The protocol was amended to remove an interim futility analysis and to specify the new nonproprietary name 'trastuzumab emtansine' (formerly T-DM1).
    29 May 2013
    The protocol was revised in order to allow for formal comparison of both trastuzumab emtansine arms, specify statistical assumptions, evaluate OS within high and low HER2 mRNA subsets, remove the clinical benefit rate (CR/PR/SD) as a redundant secondary endpoint, clarify committee procedures, further update the schedule of assessments, and add the option for participants to cross over to the best treatment arm if OS was more favorable in one of the trastuzumab emtansine arms.
    01 Nov 2013
    The protocol was modified to add safety guidance on hepatotoxicity, including updated language for hemorrhage and Hy's Law.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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