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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial To Evaluate the Efficacy And Safety Of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2007-002997-72
    Trial protocol
    		 FI   DE   GB   ES   FR   IT   LV  
    Global end of trial date
    23 Nov 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Dec 2019
    First version publication date
    06 Aug 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    TOC4129g/WO20698
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00567190
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 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
    Final
    Date of interim/final analysis
    23 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare progression-free survival (PFS) based on tumor assessments by an independent review facility (IRF) between participants in two treatment arms: Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel.
    Protection of trial subjects
    This study was conducted in full conformance with the principles of the Declaration of Helsinki and its subsequent amendments or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the participant. The study adhered to the principles outlined in the Guideline for Good Clinical Practice ICH Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the participant. In other countries where guidelines for good clinical practice existed, the sponsor and the investigators were to strictly ensure adherence to the stated provisions. For each potential participant, written informed consent was obtained prior to the performance of any study related procedures and after the aims, methods, anticipated benefits, and potential hazards of the study were adequately explained. The protocol and any accompanying material provided to the participant (such as participant information sheets or descriptions of the study used to obtain informed consent) were approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB) before starting the study. Protocol amendments were also approved by IECs/IRBs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Regulatory reason, Efficacy
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 100
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    China: 13
    Country: Number of subjects enrolled
    Costa Rica: 6
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Ecuador: 1
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Guatemala: 5
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Japan: 53
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 3
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Philippines: 30
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Russian Federation: 71
    Country: Number of subjects enrolled
    Singapore: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 94
    Country: Number of subjects enrolled
    Spain: 58
    Country: Number of subjects enrolled
    Thailand: 38
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    United States: 116
    Worldwide total number of subjects
    808
    EEA total number of subjects
    232
    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)
    681
    From 65 to 84 years
    126
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1196 patients were screened for the study, of whom a total of 808 subjects were randomized to one of the two treatment arms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pertuzumab + Trastuzumab + Docetaxel
    Arm description
    		 Subjects randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered as an intravenous (IV) loading dose of 840 milligrams (mg) at Cycle 1 then at a dose of 420 mg at all subsequent cycles (1 cycle was 21 days) until investigator-assessed radiographic or clinical evidence of progressive disease (PD), unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herclon, Herceptin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an IV loading dose of 8 mg/kg at Cycle 1 and at a dose of 6 mg/kg at all subsequent cycles (1 cycle was 21 days) until investigator-assessed radiographic or clinical evidence of PD, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere, Docecad, Docefrez
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered as an IV dose of 75 milligrams per square metre of body surface area (mg/m^2) for at least 6 cycles (1 cycle was 21 days). For subjects who tolerated at least one cycle without any significant toxicity, the docetaxel dose was increased to 100 mg/m^2 at the investigator’s discretion. On or prior to Cycle 6, docetaxel was only discontinued for PD or unacceptable toxicity. After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician.

    Arm title
    		 Placebo + Trastuzumab + Docetaxel
    Arm description
    		 Subjects randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The placebo formulation was equivalent to pertuzumab without the active agent. Subjects received placebo IV at each treatment cycle (once every 3 weeks) until investigator-assessed radiographic or clinical evidence of PD, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herclon, Herceptin
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an IV loading dose of 8 mg/kg at Cycle 1 and at a dose of 6 mg/kg at all subsequent cycles (1 cycle was 21 days) until investigator-assessed radiographic or clinical evidence of PD, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere, Docecad, Docefrez
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel was administered as an IV dose of 75 milligrams per square metre of body surface area (mg/m^2) for at least 6 cycles (1 cycle was 21 days). For subjects who tolerated at least one cycle without any significant toxicity, the docetaxel dose was increased to 100 mg/m^2 at the investigator’s discretion. On or prior to Cycle 6, docetaxel was only discontinued for PD or unacceptable toxicity. After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician.

    Number of subjects in period 1
    		Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Started
    402
    406
    Did Not Receive Any Study Treatment
    2 [1]
    2 [2]
    Received At Least One Dose of Pertuzumab
    399
    9 [3]
    Received Placebo at Every Cycle
    1 [4]
    395
    Completed
    119
    73
    Not completed
    283
    333
         Withdrew Consent or Lost to Follow-up
    48
    53
         Death
    235
    280
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 2 subjects randomized to the Pertuzumab arm withdrew from the study before receiving any study treatment.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 2 subjects randomized to the Placebo arm withdrew from the study before receiving any study treatment.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 9 subjects randomized to the Placebo arm actually received at least one dose of pertuzumab in error.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: One subject randomized to the Pertuzumab arm actually received placebo in error at every treatment cycle.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Docetaxel
    Reporting group description
    		 Subjects randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Reporting group title
    Placebo + Trastuzumab + Docetaxel
    Reporting group description
    		 Subjects randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Reporting group values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel Total
    Number of subjects
    		 402 406 808
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 342 339 681
        From 65 to 84 years
    		 60 66 126
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.4 ± 10.94 53.5 ± 11.35 -
    Gender categorical
    Units: Subjects
        Female
    		 402 404 806
        Male
    		 0 2 2
    Region
    Units: Subjects
        Asia
    		 125 128 253
        Europe
    		 154 152 306
        North America
    		 67 68 135
        South America
    		 56 58 114
    Prior Treatment Status
    Units: Subjects
        Adjuvant or Neo-Adjuvant Therapy
    		 184 192 376
        De Novo
    		 218 214 432
    Independent-Review Facility (IRF)-Determined Disease Status at Screening
    A subject was deemed to have measurable disease if they had at least 1 target lesion at screening. Target lesions (maximum of 5 per organ and 10 in total) were selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). Any subjects with non-target lesions only were deemed to have non-measurable disease. The IRF did not evaluate baseline tumor assessments for any subject without a post-baseline tumor assessment.
    Units: Subjects
        Measurable Disease
    		 343 336 679
        Non-Measurable Disease
    		 44 43 87
        Not Evaluated
    		 15 27 42

    End points

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    End points reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Docetaxel
    Reporting group description
    		 Subjects randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Reporting group title
    Placebo + Trastuzumab + Docetaxel
    Reporting group description
    		 Subjects randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Subject analysis set title
    Placebo + Trastuzumab + Docetaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This is the placebo safety population, which includes subjects who received study treatment with placebo at every cycle. Subjects received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Subject analysis set title
    Pertuzumab + Trastuzumab + Docetaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This is the pertuzumab safety population, which includes subjects who received at least one dose of study treatment with pertuzumab. Subjects received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Subject analysis set title
    Crossover From Placebo to Pertuzumab
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Fifty of 406 subjects (12.3%) randomized to the placebo treatment group whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Subjects received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Primary: Progression-Free Survival (PFS) Determined by an Independent Review Facility

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    End point title
    		 Progression-Free Survival (PFS) Determined by an Independent Review Facility
    End point description
    PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Subjects without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment. Subjects with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
    End point type
    Primary
    End point timeframe
    Tumor assessments every 9 weeks from randomization to IRF-determined PD or death from any cause, whichever occurred first, up to the primary completion date (up to 3 years, 3 months)
    End point values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Number of subjects analysed
    402 [1]
    406 [2]
    Units: Months
        median (confidence interval 95%)
    18.5 (15 to 23)
    12.4 (10 to 13)
    Notes
    [1] - Intent-to-Treat (ITT) Population: all randomized subjects were included.
    [2] - ITT Population: all randomized subjects were included.
    Statistical analysis title
    		 PFS by IRF - Stratified
    Statistical analysis description
    The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.75
    Notes
    [3] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.
    [4] - Stratified by prior treatment status and region. Tested at two-sided 5% significance level.
    Statistical analysis title
    		 PFS by IRF - Unstratified
    Statistical analysis description
    The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Log Rank (unstratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.76
    Notes
    [5] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.
    [6] - Unstratified and tested at two-sided 5% significance level

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) was defined as time from randomization to death from any cause, using Kaplan-Meier methodology. Survival data was collected every 18 weeks during the post-treatment follow-up period until death, loss to follow-up, or withdrawal of consent; immediately prior to final OS analysis data cutoff, every subject on study was contacted to confirm current status. Those who were alive, lost to follow up, or withdrew consent were censored at the latest date they participated in the study; those without post-baseline data were censored at 1 day. OS analyses were planned to take place at the primary completion date (First Interim OS Analysis), after 385 deaths (Event-Driven Final OS Analysis), and at the end of study (End-of-Study OS Analysis). A second interim OS analysis was planned due to a formal request from the EMA. '99999' indicates median and/or 95% confidence interval values could not be determined because they were larger than the maximum follow-up time at analysis.
    End point type
    Secondary
    End point timeframe
    From randomization (first subject enrolled date: 12-Feb-2008) to death from any cause, up to each respective data analysis cut-off date (First: 13-May-2011; Second: 14-May-2012; Event-Driven Final: 11-Feb-2014; End-of-Study: 23-Nov-2018)
    End point values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Number of subjects analysed
    402 [7]
    406 [8]
    Units: Months
    median (confidence interval 95%)
        End-of-Study OS Analysis (23-Nov-2018)
    57.1 (50 to 72)
    40.8 (36 to 48)
        Event-Driven Final OS Analysis (11-Feb-2014)
    56.5 (49 to 99999)
    40.8 (36 to 48)
        Second Interim OS Analysis (14-May-2012)
    99999 (42 to 99999)
    37.6 (34 to 99999)
        First Interim OS Analysis (13-May-2011)
    99999 (99999 to 99999)
    99999 (30 to 99999)
    Notes
    [7] - ITT Population
    [8] - ITT Population
    Statistical analysis title
    		 End-of-Study OS Analysis (23-Nov-2018)
    Statistical analysis description
    This end-of-study OS analysis is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.82
    Notes
    [9] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.
    [10] - Stratified by prior treatment status and region; p-value is exploratory.
    Statistical analysis title
    		 Event-Driven Final OS Analysis (11-Feb-2014)
    Statistical analysis description
    This final OS analysis was event-driven and planned to take place after a total of 385 deaths had occurred. It is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0002 [12]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 0.84
    Notes
    [11] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.
    [12] - Stratified by prior treatment status and region; p-value is exploratory.
    Statistical analysis title
    		 Second Interim OS Analysis (14-May-2012)
    Statistical analysis description
    For this second interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.739, p≤0.0138.
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0008 [14]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.84
    Notes
    [13] - Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.
    [14] - Stratified by prior treatment status and region. The threshold for statistical significance was HR≤0.739, p≤0.0138.
    Statistical analysis title
    		 First Interim OS Analysis (13-May-2011)
    Statistical analysis description
    For this first interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.603, p≤0.0012.
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.005 [16]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.88
    Notes
    [15] - Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.
    [16] - Stratified by prior treatment status and region. The threshold for statistical significance was HR≤0.603, p≤0.0012.

    Secondary: Progression-Free Survival (PFS) Determined by the Investigator

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    End point title
    		 Progression-Free Survival (PFS) Determined by the Investigator
    End point description
    PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by the investigator using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Subjects without PD or who had not died within 18 weeks of their last investigator-determined, progression-free tumor assessment were censored at the date of the last investigator tumor assessment. Subjects with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
    End point type
    Secondary
    End point timeframe
    Tumor assessments every 9 weeks from randomization to investigator-determined PD or death from any cause, whichever occurred first (median [range] time on study in Pertuzumab arm vs. Placebo arm: 201.8 [0.7-520.0] weeks vs. 138.0 [0.4-514.7] weeks)
    End point values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Number of subjects analysed
    402 [17]
    406 [18]
    Units: Months
        median (confidence interval 95%)
    18.7 (17 to 22)
    12.4 (10 to 14)
    Notes
    [17] - ITT Population
    [18] - ITT Population
    Statistical analysis title
    		 PFS by Investigator - Stratified
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    808
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.81
    Notes
    [19] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.
    [20] - Stratified by prior treatment status and region

    Secondary: Objective Response Determined by an Independent Review Facility

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    End point title
    		 Objective Response Determined by an Independent Review Facility
    End point description
    An objective response was defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as determined by an independent review facility (IRF) using RECIST v1.0 on two consecutive occasions ≥4 weeks apart. For target lesions, CR: disappearance of all target lesions; PR: ≥30% decrease in the sum of the longest diameter (LD) of target lesions (baseline sum LD as reference); PD: ≥20% increase in the sum of the LD of target lesions (smallest sum of the LD recorded as reference) or appearance of ≥1 new lesion; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for PD. For non-target lesions, CR: disappearance of all non-target lesions; Incomplete/SD: persistence of ≥1 non-target lesions; PD: unequivocal progression of existing non-target lesions. 95% confidence intervals (CI) were calculated only for clinical responses using the Pearson-Clopper method; '0.099999' and '999999'=95% CIs not calculated.
    End point type
    Secondary
    End point timeframe
    Tumor assessments every 9 weeks from Baseline until IRF-determined progressive disease (PD) or death from any cause, up to the primary completion date (up to 3 years, 3 months)
    End point values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Number of subjects analysed
    343 [21]
    336 [22]
    Units: Percentage of subjects
    number (confidence interval 95%)
        Objective Response (CR + PR)
    80.2 (75.6 to 84.3)
    69.3 (64.1 to 74.2)
        Complete Response (CR)
    5.5 (3.4 to 8.5)
    4.2 (2.3 to 6.9)
        Partial Response (PR)
    74.6 (69.7 to 79.2)
    65.2 (59.8 to 70.3)
        Stable Disease (SD)
    14.6 (11.0 to 18.8)
    20.8 (16.6 to 25.6)
        Progressive Disease (PD)
    3.8 (2.0 to 6.4)
    8.3 (5.6 to 11.8)
        Unable to Assess (UA)
    0.6 (0.1 to 2.1)
    0.6 (0.1 to 2.1)
        Missing (No Assessment)
    0.9 (0.099999 to 999999)
    0.9 (0.099999 to 999999)
    Notes
    [21] - ITT Population: only subjects with IRF-determined measurable disease at baseline were included.
    [22] - ITT Population: only subjects with IRF-determined measurable disease at baseline were included.
    Statistical analysis title
    		 Difference in Objective Response (CR + PR)
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.0011 [24]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in Objective Response Rates
    Point estimate
    10.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.2
         upper limit
    		 17.5
    Notes
    [23] - Difference in the objective response rates between arms is calculated as Pertuzumab arm minus Placebo arm. The 95% CI was calculated using the Hauck-Anderson method.
    [24] - Stratified by prior treatment status and region.
    Statistical analysis title
    		 Odds Ratio for Objective Response (CR + PR)
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.26
         upper limit
    		 2.54
    Notes
    [25] - Odds ratio for objective response is comparing Pertuzumab arm with Placebo arm.

    Secondary: Duration of Objective Response Determined by an Independent Review Facility

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    End point title
    		 Duration of Objective Response Determined by an Independent Review Facility
    End point description
    Duration of objective response (estimated using the Kaplan-Meier approach) was defined as the time from the initial confirmed complete response (CR) or partial response (PR), the date of tumor assessment at which the CR/PR was first detected by the independent review facility (IRF) using RECIST version 1.0, until the date of IRF-determined progressive disease (PD) or death from any cause within 18 weeks of the last tumor assessment, whichever occurred first. If the visit when the initial CR or PR was observed spanned multiple dates, the latest date was used. Only subjects in the ITT analysis population with an IRF-determined objective response (CR or PR), observed prior to IRF-assessed PD, death or next line of anti-cancer therapy, were included in the analysis. Subjects who did not progress or die after they had a confirmed response were censored at the date of their last IRF-evaluable tumor measurement.
    End point type
    Secondary
    End point timeframe
    From initial IRF-confirmed CR/PR until IRF-determined PD, death from any cause, or next line of anti-cancer therapy (whichever occurred earliest), up to the primary completion date (up to 3 years, 3 months)
    End point values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Number of subjects analysed
    275 [26]
    233 [27]
    Units: Weeks
        median (confidence interval 95%)
    87.6 (71 to 106)
    54.1 (46 to 64)
    Notes
    [26] - ITT Population: only subjects with an objective response were included in the analysis
    [27] - ITT Population: only subjects with an objective response were included in the analysis
    Statistical analysis title
    		 Hazard Ratio
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.85
    Notes
    [28] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.

    Secondary: Time to Symptom Progression

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    End point title
    		 Time to Symptom Progression
    End point description
    Time to symptom progression was defined as the time from randomization to the first symptom progression as evaluated from the Functional Assessment of Cancer Therapy-for participants with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical Well-being, Functional Well-being, and Additional Concerns for breast cancer participants (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 (“not at all”) to 4 (“very much”). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.
    End point type
    Secondary
    End point timeframe
    Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months)
    End point values
    		 Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
    Number of subjects analysed
    402 [29]
    404 [30]
    Units: Weeks
        median (confidence interval 95%)
    18.4 (18 to 27)
    18.3 (18 to 27)
    Notes
    [29] - ITT Population: analysis included only female subjects.
    [30] - ITT Population: analysis included only female subjects.
    Statistical analysis title
    		 Time to Symptom Progression - FACT-B
    Comparison groups
    Pertuzumab + Trastuzumab + Docetaxel v Placebo + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    806
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.7161 [32]
    Method
    		 Log Rank (stratified)
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.16
    Notes
    [31] - Hazard ratio is comparing Pertuzumab arm with Placebo arm.
    [32] - Stratified by prior treatment status and region

    Secondary: Overall Number of Subjects Who Experienced At Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period

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    End point title
    		 Overall Number of Subjects Who Experienced At Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period
    End point description
    An adverse event’s (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0); if the AE was not specifically listed, the following grades of severity were used: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening or disabling; and Grade 5 = death. Severe and serious are not synonymous. Severity refers to the intensity of an AE, whereas a serious AE must meet criteria set out in the protocol; both were independently assessed for each AE. Only the most severe intensity was counted for multiple occurrences of the same AE in one subject. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for subjects who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
    End point type
    Secondary
    End point timeframe
    Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396 [33]
    408 [34]
    50 [35]
    Units: Subjects
        At Least One Serious AE - All Grades
    116
    160
    10
        At Least One Non-Serious AE - All Grades
    386
    400
    45
        At Least One AE - All Grades
    391
    408
    47
        At Least One AE - Grade 1
    368
    386
    44
        At Least One AE - Grade 2
    350
    383
    34
        At Least One AE - Grade 3
    229
    264
    11
        At Least One AE - Grade 4
    158
    167
    1
        At Least One AE - Grade 5
    12
    8
    1
    Notes
    [33] - Safety Population
    [34] - Safety Population
    [35] - Safety Population
    No statistical analyses for this end point

    Secondary: Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3-5) per 100 Patient-Years of Exposure During the Treatment Period

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    End point title
    		 Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3-5) per 100 Patient-Years of Exposure During the Treatment Period
    End point description
    The severity of an adverse event (AE), including serious and non-serious AEs, was assessed according to the NCI-CTCAE version 3.0; if the AE was not specifically listed, the following grades of severity were used: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening or disabling; and Grade 5 is death. Multiple occurrences of the same AE in one subject were counted multiple times. Only AEs that started during the overall study treatment period were included. The cutoff date for inclusion of events and for calculation of patient-years was the date of the most recent follow-up of the subject, defined as the last available date during the treatment period, excluding pre-treatment and safety follow-up data. Confidence intervals were calculated assuming the number of events followed a Poisson distribution. Data reported prior to the date of first crossover treatment were included under the Placebo arm for subjects who crossed over from placebo to pertuzumab.
    End point type
    Secondary
    End point timeframe
    From Baseline to 42 days after the last dose of study treatment (total patient-years of exposure on study treatment in Placebo arm vs. Pertuzumab arm: 526.81 patient-years vs. 989.88 patient-years)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel
    Number of subjects analysed
    396 [36]
    408 [37]
    Units: Events per 100 patient-years
    number (confidence interval 90%)
        All Grades
    1720.2 (1690.6 to 1750.2)
    1203.0 (1184.9 to 1221.3)
        Grades 3 to 5
    225.3 (214.7 to 236.4)
    131.7 (125.8 to 137.9)
    Notes
    [36] - Safety Population
    [37] - Safety Population
    No statistical analyses for this end point

    Secondary: Cardiac-Related AEs to Monitor: Percentage of Subjects Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious Adverse Event Suggestive of Congestive Heart Failure by Severity During the Treatment Period

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    End point title
    		 Cardiac-Related AEs to Monitor: Percentage of Subjects Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious Adverse Event Suggestive of Congestive Heart Failure by Severity During the Treatment Period
    End point description
    Cardiac-related adverse events (AEs) to monitor during the study included investigator-assessed symptomatic left ventricular dysfunction (LVD), any LVD, or a serious adverse event (SAE) suggestive of congestive heart failure (CHF). All cardiac-related AEs were graded for severity according to NCI-CTCAE v3.0. Asymptomatic (Grades 1-2) and symptomatic (Grades 3-5) left ventricular systolic dysfunction (LVSD) both coded to the MedDRA preferred term LVD. Investigator-assessed events of symptomatic LVD were also graded for severity of symptoms according to Classes I (least severe) to IV (most severe) of the New York Heart Association (NYHA) Classification. SAEs suggestive of CHF were identified as serious events from the Standardized MedDRA Query (SMQ) (Wide) 'Cardiac Failure'. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
    End point type
    Secondary
    End point timeframe
    Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396 [38]
    408 [39]
    50 [40]
    Units: Percentage of subjects
    number (not applicable)
        Symptomatic LVD(Investigator)-All NYHA Classes
    1.8
    1.5
    2.0
        Symptomatic LVD(Investigator)-NYHA Classes III/IV
    1.0
    1.0
    2.0
        Any LVD - All NCI-CTCAE Grades
    8.6
    7.8
    6.0
        Any LVD - NCI-CTCAE Grade ≥3
    3.3
    1.5
    4.0
        SAE Suggestive of CHF - All NCI-CTCAE Grades
    2.0
    2.0
    2.0
        SAE Suggestive of CHF - NCI-CTCAE Grade ≥3
    1.8
    1.7
    2.0
    Notes
    [38] - Safety Population
    [39] - Safety Population
    [40] - Safety Population
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period

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    End point title
    		 Percentage of Subjects Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period
    End point description
    The clinical diagnoses listed in this table, excluding cardiac safety (summarized separately), were also selected as adverse events (AEs) to monitor based on clinical and nonclinical data for pertuzumab and the safety profile established for trastuzumab, monoclonal antibodies in general, and potential effects associated with HER receptor inhibition. Search strategies were defined by single or aggregate MedDRA Preferred Terms (PT) through Standardized MedDRA Queries (SMQ), where possible, or based on Roche AE Group Terms (AEGT). Diarrhoea AEs: High-Level Term (HLT) 'Diarrhoea (excl. infective)' and PT 'Diarrhoea infectious'. Leukopenic and Febrile Neutropenic Infections: AEs from 'Infections & Infestations' with start ≤14 days after start date of Grade ≥3 AEs in SMQ(narrow) 'Leukopenia' or PT 'Febrile neutropenia', respectively. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
    End point type
    Secondary
    End point timeframe
    Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396
    408
    50
    Units: Percentage of subjects
    number (not applicable)
        Diarrhoea (HLT+PT) - All Grades
    48.2
    68.6
    50.0
        Diarrhoea (HLT+PT) - Grade ≥3
    5.1
    9.8
    2.0
        Rash (AEGT) - All Grades
    39.1
    52.2
    36.0
        Rash (AEGT) - Grade ≥3
    1.5
    3.7
    0.0
        Leukopenia (SMQ-narrow) - All Grades
    58.3
    63.0
    2.0
        Leukopenia (SMQ-narrow) - Grade ≥3
    53.3
    58.3
    0.0
        Leukopenic Infection (PTs) - All Grades
    9.6
    13.0
    0.0
        Leukopenic Infection (PTs) - Grade ≥3
    2.3
    4.4
    0.0
        Febrile Neutropenic Infection (PTs) - All Grades
    0.8
    3.4
    0.0
        Febrile Neutropenic Infection (PTs) - Grade ≥3
    0.3
    1.5
    0.0
        Anaphylaxis and Hypersensitivity (AEGT)-All Grades
    9.3
    11.8
    2.0
        Anaphylaxis and Hypersensitivity (AEGT)-Grade ≥3
    2.5
    2.2
    0.0
        Interstitial Lung Disease (SMQ-narrow) -All Grades
    1.5
    2.5
    2.0
        Interstitial Lung Disease (SMQ-narrow) -Grade ≥3
    0.5
    0.7
    0.0
        QT Prolongation (SMQ-wide) - All Grades
    1.3
    3.9
    0.0
        QT Prolongation (SMQ-wide) - Grade ≥3
    0.3
    1.7
    0.0
        Mucositis (AEGT) - All Grades
    38.9
    51.0
    24.0
        Mucositis (AEGT) - Grade ≥3
    2.0
    3.4
    0.0
        Drug-Related Hepatic Disorder(SMQ-wide)-All Grades
    10.9
    11.5
    0.0
        Drug-Related Hepatic Disorder (SMQ wide)-Grade ≥3
    1.3
    2.0
    0.0
    No statistical analyses for this end point

    Secondary: Overall Percentage of Subjects Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication

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    End point title
    		 Overall Percentage of Subjects Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication
    End point description
    Subjects could continue study treatment with pertuzumab/placebo plus trastuzumab when docetaxel was discontinued due to an adverse event (AE). Discontinuation of pertuzumab/placebo or trastuzumab due to an AE led to discontinuation of all study medication. The percentage of subjects who discontinued any study medication due to an AE includes those who discontinued all study medication and those who discontinued docetaxel only and then continued on targeted therapy (note that some of these subjects may have subsequently discontinued all treatment due to a separate AE). Multiple occurrences of the same AE in one subject was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for subjects who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
    End point type
    Secondary
    End point timeframe
    Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396
    408
    50
    Units: Percentage of subjects
    number (not applicable)
        AE Leading to Discontinuation-Any Study Medication
    28.8
    32.1
    10.0
        AE Leading to Discontinuation-All Study Medication
    6.1
    9.6
    8.0
    No statistical analyses for this end point

    Secondary: Overall Percentage of Subjects Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication

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    End point title
    		 Overall Percentage of Subjects Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication
    End point description
    Pertuzumab, trastuzumab, and docetaxel administration could have been delayed to assess or treat adverse events. Docetaxel dose reduction was allowed for myelosuppression, hepatic dysfunction, and other toxicities. No dose reduction was allowed for pertuzumab or trastuzumab. Multiple occurrences of the same adverse event in one subject was counted only once. Adverse events reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for subjects who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks
    End point type
    Secondary
    End point timeframe
    Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396
    408
    50
    Units: Percentage of subjects
        number (not applicable)
    54.8
    65.0
    32.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period

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    End point title
    		 Percentage of Subjects Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period
    End point description
    The post-treatment period was defined as the period following the treatment discontinuation visit. Only the following new adverse events (AEs) should have been reported during the post-treatment follow-up period: 1. Cardiac events (regardless of causality or seriousness) that started up to 1 year after the last dose, except for symptomatic left ventricular systolic dysfunction (regardless of causality) that started up to 3 years after the last dose; and 2. Treatment-related serious AEs, regardless of start date. AEs are listed by Medical Dictionary for Regulatory Activities, Version 21.1 (MedDRA v21.1) System Organ Class (SOC) and Preferred Term (PT); PTs fall under the SOC that is listed immediately above it in the table. Multiple occurrences of the same AE in one subject was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for subjects who crossed over from placebo to pertuzumab.
    End point type
    Secondary
    End point timeframe
    From Day 43 after discontinuation of all study medication up to end of the post-treatment follow-up period (up to 3 years)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396 [41]
    408 [42]
    50 [43]
    Units: Percentage of subjects
    number (not applicable)
        Total with at Least One AE During Post-Treatment
    4.5
    4.2
    6.0
        Cardiac Disorders (SOC)
    2.0
    2.2
    2.0
        Left Ventricular Dysfunction (PT)
    1.5
    1.2
    2.0
        Cardiac Failure (PT)
    0.0
    0.5
    0.0
        Bundle Branch Block Left (PT)
    0.0
    0.2
    0.0
        Cardiopulmonary Failure (PT)
    0.3
    0.0
    0.0
        Myocardial Ischaemia (PT)
    0.3
    0.0
    0.0
        Pericardial Effusion (PT)
    0.0
    0.2
    0.0
        Prinzmetal Angina (PT)
    0.3
    0.0
    0.0
        General Disorders & Admin. Site Conditions (SOC)
    0.8
    0.5
    0.0
        Oedema Peripheral (PT)
    0.5
    0.2
    0.0
        Asthenia (PT)
    0.3
    0.0
    0.0
        Influenza Like Illness (PT)
    0.0
    0.2
    0.0
        Infections & Infestations (SOC)
    0.3
    0.2
    4.0
        Influenza (PT)
    0.0
    0.0
    2.0
        Viral Infection (PT)
    0.0
    0.0
    2.0
        Abscess Limb (PT)
    0.0
    0.2
    0.0
        Nasopharyngitis (PT)
    0.3
    0.0
    0.0
        Subcutaneous Abscess (PT)
    0.0
    0.2
    0.0
        Musculoskeletal & Connective Tissue Disorders(SOC)
    0.3
    0.0
    2.0
        Back Pain (PT)
    0.0
    0.0
    2.0
        Pain in Extremity (PT)
    0.3
    0.0
    0.0
        Nervous System Disorders (SOC)
    0.5
    0.5
    0.0
        Neuropathy Peripheral (PT)
    0.3
    0.2
    0.0
        Cognitive Disorder (PT)
    0.3
    0.0
    0.0
        Dizziness (PT)
    0.0
    0.2
    0.0
        Headache (PT)
    0.0
    0.2
    0.0
        Respiratory, Thoracic & Mediastinal Disorders(SOC)
    0.5
    0.2
    0.0
        Cough (PT)
    0.3
    0.0
    0.0
        Dyspnoea (PT)
    0.3
    0.0
    0.0
        Rhinitis Allergic (PT)
    0.0
    0.2
    0.0
        Skin & Subcutaneous Tissue Disorders (SOC)
    0.3
    0.5
    0.0
        Erythema (PT)
    0.0
    0.2
    0.0
        Nail Disorder (PT)
    0.3
    0.0
    0.0
        Rash Macular (PT)
    0.0
    0.2
    0.0
        Blood & Lymphatic System Disorders (SOC)
    0.3
    0.2
    0.0
        Febrile Neutropenia (PT)
    0.3
    0.0
    0.0
        Leukopenia (PT)
    0.0
    0.2
    0.0
        Gastrointestinal Disorders (SOC)
    0.0
    0.5
    0.0
        Diarrhoea (PT)
    0.0
    0.2
    0.0
        Stomatitis (PT)
    0.0
    0.2
    0.0
        Endocrine Disorders (SOC)
    0.3
    0.0
    0.0
        Thyroid Mass (PT)
    0.3
    0.0
    0.0
        Eye Disorders (SOC)
    0.3
    0.0
    0.0
        Retinal Detachment (PT)
    0.3
    0.0
    0.0
        Immune System Disorders (SOC)
    0.0
    0.2
    0.0
        Iodine Allergy (PT)
    0.0
    0.2
    0.0
        Investigations (SOC)
    0.3
    0.0
    0.0
        Aspartate Aminotransferase Increased (PT)
    0.3
    0.0
    0.0
        Renal & Urinary Disorders (SOC)
    0.0
    0.2
    0.0
        Dysuria (PT)
    0.0
    0.2
    0.0
        Reproductive System & Breast Disorders (SOC)
    0.0
    0.2
    0.0
        Breast Induration (PT)
    0.0
    0.2
    0.0
        Vascular Disorders (SOC)
    0.0
    0.2
    0.0
        Venous Thrombosis (PT)
    0.0
    0.2
    0.0
    Notes
    [41] - Safety Population
    [42] - Safety Population
    [43] - Safety Population
    No statistical analyses for this end point

    Secondary: Percentage of Subjects by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period

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    End point title
    		 Percentage of Subjects by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period
    End point description
    All subjects were required to have an left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Data reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for subjects who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
    End point type
    Secondary
    End point timeframe
    Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    378 [44]
    394 [45]
    49 [46]
    Units: Percentage of subjects
    number (not applicable)
        LVEF Increase/No Change/Decrease FromBL <10%Points
    66.7
    63.2
    61.2
        LVEF <50% and Decrease From BL ≥10% to <15% Points
    2.4
    1.8
    0
        LVEF <50% and Decrease From BL ≥15% Points
    5.0
    5.3
    6.1
        LVEF ≥50% and Decrease From BL ≥10% Points
    25.1
    29.2
    30.6
        No Baseline (BL) LVEF Value
    0.8
    0.5
    2.0
    Notes
    [44] - Safety Population
    [45] - Safety Population
    [46] - Safety Population
    No statistical analyses for this end point

    Secondary: Baseline LVEF Value and Change From Baseline at Maximum Absolute Decrease in LVEF Value During the Treatment Period

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    End point title
    		 Baseline LVEF Value and Change From Baseline at Maximum Absolute Decrease in LVEF Value During the Treatment Period
    End point description
    All subjects were required to have a left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Only data reported prior to the date of first crossover treatment were included for subjects who crossed over from placebo to open-label pertuzumab. Subjects with evaluable LVEF assessments at baseline (BL) or at BL and post-BL (for change in LVEF from BL at maximum decrease value) were included in the analyses.
    End point type
    Secondary
    End point timeframe
    Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel
    Number of subjects analysed
    396 [47]
    408 [48]
    Units: Percentage points of LVEF
    arithmetic mean (standard deviation)
        Baseline (BL) LVEF Value (n=393,406)
    65.6 ± 6.51
    64.8 ± 6.71
        Change from BL: LVEF Maximum Decrease (n=375,392)
    -7.3 ± 7.15
    -7.5 ± 7.75
    Notes
    [47] - Safety Population
    [48] - Safety Population
    Statistical analysis title
    		 Wilcoxon Test of Maximum Decrease in LVEF From BL
    Comparison groups
    Placebo + Trastuzumab + Docetaxel v Pertuzumab + Trastuzumab + Docetaxel
    Number of subjects included in analysis
    804
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7174
    Method
    		 Wilcoxon Rank-Sum Test
    Confidence interval

    Secondary: Percentage of Subjects with Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period

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    End point title
    		 Percentage of Subjects with Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
    End point description
    Clinical laboratory tests for blood biochemistry parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. The 'n' in category titles represent number of subjects per arm with at least one valid laboratory value, in order from left to right column. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. ALP = alkaline phosphatase; GGT = gamma-glutamyl transferase; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase
    End point type
    Secondary
    End point timeframe
    On Day 1 of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396 [49]
    408 [50]
    50 [51]
    Units: Percentage of subjects
    number (not applicable)
        Albumin (g/L) - Low, Any Grade (Gr.)(n=385,396,49)
    42.3
    49.5
    30.6
        Albumin (g/L) - Low, Gr. 1 (n=385,396,49)
    29.4
    33.3
    20.4
        Albumin (g/L) - Low, Gr. 2 (n=385,396,49)
    11.9
    14.6
    8.2
        Albumin (g/L) - Low, Gr. 3 (n=385,396,49)
    1.0
    1.5
    2.0
        Albumin (g/L) - Low, Gr. 4 (n=385,396,49)
    0.0
    0.0
    0.0
        ALP (U/L) - High, Any Gr. (n=388,400,49)
    47.4
    52.5
    34.7
        ALP (U/L) - High, Gr. 1 (n=388,400,49)
    40.7
    44.3
    34.7
        ALP (U/L) - High, Gr. 2 (n=388,400,49)
    4.9
    6.0
    0.0
        ALP (U/L) - High, Gr. 3 (n=388,400,49)
    1.8
    2.3
    0.0
        ALP (U/L) - High, Gr. 4 (n=388,400,49)
    0.0
    0.0
    0.0
        Calcium (mmol/L) - Low, Any Gr. (n=387,399,49)
    40.3
    50.9
    28.6
        Calcium (mmol/L) - Low, Gr. 1 (n=387,399,49)
    27.6
    34.8
    22.4
        Calcium (mmol/L) - Low, Gr. 2 (n=387,399,49)
    11.6
    12.3
    0.0
        Calcium (mmol/L) - Low, Gr. 3 (n=387,399,49)
    0.8
    1.8
    2.0
        Calcium (mmol/L) - Low, Gr. 4 (n=387,399,49)
    0.3
    2.0
    4.1
        Calcium (mmol/L) - High, Any Gr. (n=387,399,49)
    14.0
    19.8
    24.5
        Calcium (mmol/L) - High, Gr. 1 (n=387,399,49)
    12.9
    16.3
    14.3
        Calcium (mmol/L) - High, Gr. 2 (n=387,399,49)
    0.0
    0.5
    2.0
        Calcium (mmol/L) - High, Gr. 3 (n=387,399,49)
    0.8
    0.5
    0.0
        Calcium (mmol/L) - High, Gr. 4 (n=387,399,49)
    0.3
    2.5
    8.2
        Creatinine (umol/L) - High, Any Gr. (n=390,402,49)
    81.3
    86.1
    77.6
        Creatinine (umol/L) - High, Gr. 1 (n=390,402,49)
    69.5
    69.4
    55.1
        Creatinine (umol/L) - High, Gr. 2 (n=390,402,49)
    11.3
    13.4
    18.4
        Creatinine (umol/L) - High, Gr. 3 (n=390,402,49)
    0.5
    1.5
    0.0
        Creatinine (umol/L) - High, Gr. 4 (n=390,402,49)
    0.0
    1.7
    4.1
        Glucose (mmol/L) - Low, Any Gr. (n=387,400,49)
    10.9
    18.8
    12.2
        Glucose (mmol/L) - Low, Gr. 1 (n=387,400,49)
    8.3
    15.3
    8.2
        Glucose (mmol/L) - Low, Gr. 2 (n=387,400,49)
    2.3
    2.3
    0.0
        Glucose (mmol/L) - Low, Gr. 3 (n=387,400,49)
    0.3
    0.5
    0.0
        Glucose (mmol/L) - Low, Gr. 4 (n=387,400,49)
    0.0
    0.8
    4.1
        Glucose (mmol/L) - High, Any Gr. (n=387,400,49)
    70.0
    74.8
    69.4
        Glucose (mmol/L) - High, Gr. 1 (n=387,400,49)
    43.4
    48.0
    53.1
        Glucose (mmol/L) - High, Gr. 2 (n=387,400,49)
    21.4
    19.5
    16.3
        Glucose (mmol/L) - High, Gr. 3 (n=387,400,49)
    5.2
    6.5
    0.0
        Glucose (mmol/L) - High, Gr. 4 (n=387,400,49)
    0.0
    0.8
    0.0
        GGT (U/L) - High, Any Gr. (n=375,394,48)
    55.7
    57.1
    29.2
        GGT (U/L) - High, Gr. 1 (n=375,394,48)
    35.5
    36.5
    18.8
        GGT (U/L) - High, Gr. 2 (n=375,394,48)
    10.9
    13.2
    8.3
        GGT (U/L) - High, Gr. 3 (n=375,394,48)
    8.0
    6.9
    2.1
        GGT (U/L) - High, Gr. 4 (n=375,394,48)
    1.3
    0.5
    0.0
        Magnesium (mmol/L) - Low, Any Gr. (n=371,398,49)
    21.3
    29.4
    16.3
        Magnesium (mmol/L) - Low, Gr. 1 (n=371,398,49)
    19.1
    24.6
    12.2
        Magnesium (mmol/L) - Low, Gr. 2 (n=371,398,49)
    1.9
    3.3
    0.0
        Magnesium (mmol/L) - Low, Gr. 3 (n=371,398,49)
    0.3
    0.8
    0.0
        Magnesium (mmol/L) - Low, Gr. 4 (n=371,398,49)
    0.0
    0.8
    4.1
        Magnesium (mmol/L) - High, Any Gr. (n=371,398,49)
    20.5
    26.4
    32.7
        Magnesium (mmol/L) - High, Gr. 1 (n=371,398,49)
    15.6
    20.1
    22.4
        Magnesium (mmol/L) - High, Gr. 2 (n=371,398,49)
    0.0
    0.0
    0.0
        Magnesium (mmol/L) - High, Gr. 3 (n=371,398,49)
    4.9
    5.5
    8.2
        Magnesium (mmol/L) - High, Gr. 4 (n=371,398,49)
    0.0
    0.8
    2.0
        Potassium (mmol/L) - Low, Any Gr. (n=389,401,49)
    20.6
    35.9
    22.4
        Potassium (mmol/L) - Low, Gr. 1 (n=389,401,49)
    0.0
    0.0
    0.0
        Potassium (mmol/L) - Low, Gr. 2 (n=389,401,49)
    17.5
    29.4
    16.3
        Potassium (mmol/L) - Low, Gr. 3 (n=389,401,49)
    2.6
    4.5
    4.1
        Potassium (mmol/L) - Low, Gr. 4 (n=389,401,49)
    0.5
    2.0
    2.0
        Potassium (mmol/L) - High, Any Gr. (n=389,401,49)
    17.2
    19.5
    26.5
        Potassium (mmol/L) - High, Gr. 1 (n=389,401,49)
    12.6
    13.7
    22.4
        Potassium (mmol/L) - High, Gr. 2 (n=389,401,49)
    3.9
    4.2
    4.1
        Potassium (mmol/L) - High, Gr. 3 (n=389,401,49)
    0.8
    1.5
    0.0
        Potassium (mmol/L) - High, Gr. 4 (n=389,401,49)
    0.0
    0.0
    0.0
        SGOT (U/L) - High, Any Gr. (n=389,400,49)
    47.3
    48.3
    34.7
        SGOT (U/L) - High, Gr. 1 (n=389,400,49)
    43.4
    42.5
    30.6
        SGOT (U/L) - High, Gr. 2 (n=389,400,49)
    2.8
    3.0
    4.1
        SGOT (U/L) - High, Gr. 3 (n=389,400,49)
    1.0
    2.5
    0.0
        SGOT (U/L) - High, Gr. 4 (n=389,400,49)
    0.0
    0.3
    0.0
        SGPT (U/L) - High, Any Gr. (n=390,400,49)
    50.0
    52.3
    38.8
        SGPT (U/L) - High, Gr. 1 (n=390,400,49)
    44.1
    43.8
    34.7
        SGPT (U/L) - High, Gr. 2 (n=390,400,49)
    4.6
    4.8
    4.1
        SGPT (U/L) - High, Gr. 3 (n=390,400,49)
    1.3
    3.5
    0.0
        SGPT (U/L) - High, Gr. 4 (n=390,400,49)
    0.0
    0.3
    0.0
        Sodium (mmol/L) - Low, Any Gr. (n=389,402,49)
    28.0
    33.6
    51.0
        Sodium (mmol/L) - Low, Gr. 1 (n=389,402,49)
    22.4
    30.1
    44.9
        Sodium (mmol/L) - Low, Gr. 2 (n=389,402,49)
    0.0
    0.0
    0.0
        Sodium (mmol/L) - Low, Gr. 3 (n=389,402,49)
    5.4
    3.0
    2.0
        Sodium (mmol/L) - Low, Gr. 4 (n=389,402,49)
    0.3
    0.5
    4.1
        Sodium (mmol/L) - High, Any Gr. (n=389,402,49)
    19.5
    25.6
    18.4
        Sodium (mmol/L) - High, Gr. 1 (n=389,402,49)
    18.3
    22.6
    14.3
        Sodium (mmol/L) - High, Gr. 2 (n=389,402,49)
    1.0
    2.2
    4.1
        Sodium (mmol/L) - High, Gr. 3 (n=389,402,49)
    0.3
    0.5
    0.0
        Sodium (mmol/L) - High, Gr. 4 (n=389,402,49)
    0.0
    0.2
    0.0
        Tot. Bilirubin (umol/L)-High,Any Gr.(n=390,401,49)
    9.0
    14.2
    14.3
        Tot. Bilirubin (umol/L)-High, Gr. 1 (n=390,401,49)
    6.7
    11.0
    12.2
        Tot. Bilirubin (umol/L)-High, Gr. 2 (n=390,401,49)
    1.8
    2.2
    0.0
        Tot. Bilirubin (umol/L)-High, Gr. 3 (n=390,401,49)
    0.5
    0.5
    0.0
        Tot. Bilirubin (umol/L)-High, Gr. 4 (n=390,401,49)
    0.0
    0.5
    2.0
        Uric Acid (umol/L) - High, Any Gr. (n=370,397,49)
    31.9
    28.5
    30.6
        Uric Acid (umol/L) - High, Gr. 1 (n=370,397,49)
    0.0
    0.0
    0.0
        Uric Acid (umol/L) - High, Gr. 2 (n=370,397,49)
    0.0
    0.0
    0.0
        Uric Acid (umol/L) - High, Gr. 3 (n=370,397,49)
    31.4
    24.7
    20.4
        Uric Acid (umol/L) - High, Gr. 4 (n=370,397,49)
    0.5
    3.8
    10.2
    Notes
    [49] - Safety Population
    [50] - Safety Population
    [51] - Safety Population
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period

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    End point title
    		 Percentage of Subjects with Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
    End point description
    Clinical laboratory tests for hematology parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. The 'n' in category titles represent number of subjects per arm with at least one valid laboratory value, in order from left to right column. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. INR = International Normalized Ratio; PTT = partial thromboplastin time; WBC = white blood cell
    End point type
    Secondary
    End point timeframe
    On Day 1 (and Day 8 for some measures) of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)
    End point values
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Number of subjects analysed
    396 [52]
    408 [53]
    50 [54]
    Units: Percentage of subjects
    number (not applicable)
        Hemoglobin (g/L) -Low,Any Grade(Gr.)(n=392,404,49)
    89.3
    92.1
    40.8
        Hemoglobin (g/L) - Low, Gr. 1 (n=392,404,49)
    51.5
    46.0
    18.4
        Hemoglobin (g/L) - Low, Gr. 2 (n=392,404,49)
    32.4
    39.9
    12.2
        Hemoglobin (g/L) - Low, Gr. 3 (n=392,404,49)
    5.4
    6.2
    10.2
        Hemoglobin (g/L) - Low, Gr. 4 (n=392,404,49)
    0.0
    0.0
    0.0
        Hemoglobin (g/L) - High, Any Gr. (n=392,404,49)
    2.6
    5.7
    8.2
        Hemoglobin (g/L) - High, Gr. 1 (n=392,404,49)
    2.3
    5.0
    4.1
        Hemoglobin (g/L) - High, Gr. 2 (n=392,404,49)
    0.3
    0.5
    0.0
        Hemoglobin (g/L) - High, Gr. 3 (n=392,404,49)
    0.0
    0.2
    4.1
        Hemoglobin (g/L) - High, Gr. 4 (n=392,404,49)
    0.0
    0.0
    0.0
        Lymphocytes (10^9/L) - Low, Any Gr. (n=391,404,49)
    66.2
    68.3
    16.3
        Lymphocytes (10^9/L) - Low, Gr. 1 (n=391,404,49)
    9.2
    9.7
    0.0
        Lymphocytes (10^9/L) - Low, Gr. 2 (n=391,404,49)
    32.7
    33.7
    8.2
        Lymphocytes (10^9/L) - Low, Gr. 3 (n=391,404,49)
    16.4
    17.1
    6.1
        Lymphocytes (10^9/L) - Low, Gr. 4 (n=391,404,49)
    7.9
    7.9
    2.0
        Lymphocytes (10^9/L)- High, Any Gr. (n=391,404,49)
    14.8
    17.8
    18.4
        Lymphocytes (10^9/L)- High, Gr. 1 (n=391,404,49)
    0.0
    0.0
    0.0
        Lymphocytes (10^9/L)- High, Gr. 2 (n=391,404,49)
    12.5
    14.1
    12.2
        Lymphocytes (10^9/L)- High, Gr. 3 (n=391,404,49)
    2.3
    3.7
    6.1
        Lymphocytes (10^9/L)- High, Gr. 4 (n=391,404,49)
    0.0
    0.0
    0.0
        Neutrophils (10^9/L)- Low, Any Gr. (n=391,404,49)
    89.3
    91.8
    4.1
        Neutrophils (10^9/L)- Low, Gr. 1 (n=391,404,49)
    1.8
    1.0
    0.0
        Neutrophils (10^9/L)- Low, Gr. 2 (n=391,404,49)
    6.4
    8.4
    0.0
        Neutrophils (10^9/L)- Low, Gr. 3 (n=391,404,49)
    20.7
    24.5
    0.0
        Neutrophils (10^9/L)- Low, Gr. 4 (n=391,404,49)
    60.4
    57.9
    4.1
        PTT (sec) - High, Any Gr. (n=28,35,3)
    21.4
    25.7
    33.3
        PTT (sec) - High, Gr. 1 (n=28,35,3)
    17.9
    5.7
    33.3
        PTT (sec) - High, Gr. 2 (n=28,35,3)
    0.0
    11.4
    0.0
        PTT (sec) - High, Gr. 3 (n=28,35,3)
    3.6
    8.6
    0.0
        PTT (sec) - High, Gr. 4 (n=28,35,3)
    0.0
    0.0
    0.0
        Platelets (10^9/L) - Low, Any Gr. (n=392,404,49)
    20.9
    22.8
    26.5
        Platelets (10^9/L) - Low, Gr. 1 (n=392,404,49)
    19.1
    19.3
    22.4
        Platelets (10^9/L) - Low, Gr. 2 (n=392,404,49)
    1.3
    1.2
    0.0
        Platelets (10^9/L) - Low, Gr. 3 (n=392,404,49)
    0.5
    0.7
    0.0
        Platelets (10^9/L) - Low, Gr. 4 (n=392,404,49)
    0.0
    1.5
    4.1
        Prothrombin Time (INR)-High,Any Gr. (n=198,216,14)
    68.2
    72.7
    78.6
        Prothrombin Time (INR)- High, Gr. 1 (n=198,216,14)
    64.1
    63.0
    64.3
        Prothrombin Time (INR)- High, Gr. 2 (n=198,216,14)
    1.5
    2.8
    0.0
        Prothrombin Time (INR)- High, Gr. 3 (n=198,216,14)
    2.5
    6.9
    14.3
        Prothrombin Time (INR)- High, Gr. 4 (n=198,216,14)
    0.0
    0.0
    0.0
        WBC (10^9/L) - Low, Any Gr. (n=392,404,49)
    93.4
    95.8
    10.2
        WBC (10^9/L) - Low, Gr. 1 (n=392,404,49)
    9.2
    8.4
    2.0
        WBC (10^9/L) - Low, Gr. 2 (n=392,404,49)
    23.5
    22.8
    6.1
        WBC (10^9/L) - Low, Gr. 3 (n=392,404,49)
    47.4
    51.0
    0.0
        WBC (10^9/L) - Low, Gr. 4 (n=392,404,49)
    13.3
    13.6
    2.1
        WBC (10^9/L) - High, Any Gr. (n=392,404,49)
    0.0
    0.7
    2.0
        WBC (10^9/L) - High, Gr. 1 (n=392,404,49)
    0.0
    0.0
    0.0
        WBC (10^9/L) - High, Gr. 2 (n=392,404,49)
    0.0
    0.0
    0.0
        WBC (10^9/L) - High, Gr. 3 (n=392,404,49)
    0.0
    0.7
    2.0
        WBC (10^9/L) - High, Gr. 4 (n=392,404,49)
    0.0
    0.0
    0.0
    Notes
    [52] - Safety Population
    [53] - Safety Population
    [54] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first treatment dose (12-Feb-2008) through end of study (23-Nov-2018) for a total safety analysis timeframe of 10 years, 9.5 months.
    Adverse event reporting additional description
    Of enrolled subjects (Pertuzumab [Ptz]: N=402, Placebo [Pla]: N=406), 2 in each arm received no treatment (total of 4), 9 in Pla arm received at least 1 dose of Ptz, and 1 in Ptz arm received Pla at every cycle; resulting in a Safety Population of Ptz: N=408 (402-2+9-1), Pla: N=396 (406-2-9+1), and 50 subjects in Pla arm crossed over to Ptz.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo + Trastuzumab + Docetaxel
    Reporting group description
    		 This is the placebo safety population, which includes subjects who received study treatment with placebo at every cycle. Subjects received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. For subjects who crossed over to receive open-label pertuzumab, adverse events (AEs) were included in the Placebo group from the day of the first placebo dose through the day just prior to the first pertuzumab dose. Any AEs occurring on the day of the first dose of pertuzumab were included in the Crossover From Placebo to Pertuzumab group.

    Reporting group title
    Pertuzumab + Trastuzumab + Docetaxel
    Reporting group description
    		 This is the pertuzumab safety population, which includes subjects who received at least one dose of study treatment with pertuzumab. Subjects received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the subject and treating physician. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.

    Reporting group title
    Crossover From Placebo to Pertuzumab
    Reporting group description
    		 Fifty of 406 subjects (12.3%) randomized to the placebo treatment group whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Subjects received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Subjects remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. Any adverse events occurring on the day of the first crossover dose of open-label pertuzumab were included in this analysis group.

    Serious adverse events
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    116 / 396 (29.29%)
    160 / 408 (39.22%)
    10 / 50 (20.00%)
         number of deaths (all causes)
    261
    238
    14
         number of deaths resulting from adverse events
    12
    8
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Colon cancer
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Endometrial cancer
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Ocular neoplasm
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Pituitary tumour benign
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 396 (0.00%)
    3 / 408 (0.74%)
    0 / 50 (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
    Hypertension
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (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
    Aortic stenosis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Vena cava thrombosis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Hypertensive crisis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Hypotension
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Venous thrombosis limb
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 396 (0.76%)
    6 / 408 (1.47%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 396 (0.51%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 396 (0.25%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    General physical health deterioration
         subjects affected / exposed
    2 / 396 (0.51%)
    0 / 408 (0.00%)
    0 / 50 (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
    Influenza like illness
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Mucosal inflammation
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Drowning
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    3 / 396 (0.76%)
    3 / 408 (0.74%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 396 (0.00%)
    3 / 408 (0.74%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast haemorrhage
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Metrorrhagia
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    4 / 396 (1.01%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 396 (0.00%)
    6 / 408 (1.47%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 396 (0.51%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Pneumothorax
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (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
    Asthma
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Pneumonitis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Respiratory failure
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Hypoxia
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Blood electrolytes abnormal
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Blood glucose increased
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Ejection fraction decreased
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 396 (0.25%)
    3 / 408 (0.74%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Contusion
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Fracture
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Post procedural discomfort
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Scapula fracture
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Tendon injury
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Thermal burn
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Tibia fracture
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Tendon rupture
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 limb fracture
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    7 / 396 (1.77%)
    6 / 408 (1.47%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    7 / 7
    6 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 396 (0.76%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 396 (0.76%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 ischaemia
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Ventricular fibrillation
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Monoparesis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 sensorimotor neuropathy
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Somnolence
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Spinal cord compression
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Syncope
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Facial paralysis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Cerebral haematoma
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Headache
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Loss of consciousness
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    20 / 396 (5.05%)
    46 / 408 (11.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    22 / 23
    48 / 48
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    Neutropenia
         subjects affected / exposed
    19 / 396 (4.80%)
    18 / 408 (4.41%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    20 / 20
    23 / 23
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 396 (0.76%)
    3 / 408 (0.74%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Leukopenia
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 396 (1.26%)
    13 / 408 (3.19%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    3 / 5
    12 / 16
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 396 (0.25%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 396 (0.51%)
    0 / 408 (0.00%)
    0 / 50 (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
    Intestinal perforation
         subjects affected / exposed
    2 / 396 (0.51%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Abdominal pain
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Colitis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Duodenal ulcer
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Enteritis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Intestinal ischaemia
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Nausea
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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 haemorrhage
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Volvulus
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Cholelithiasis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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 failure
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Drug eruption
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (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
    Haematuria
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Acute kidney injury
         subjects affected / exposed
    2 / 396 (0.51%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 396 (0.00%)
    0 / 408 (0.00%)
    1 / 50 (2.00%)
         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 and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 396 (0.25%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Muscular weakness
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Neck pain
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    11 / 396 (2.78%)
    7 / 408 (1.72%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 11
    2 / 7
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 396 (0.51%)
    10 / 408 (2.45%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 396 (0.25%)
    4 / 408 (0.98%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 396 (0.51%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    3 / 396 (0.76%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 396 (0.00%)
    4 / 408 (0.98%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 396 (0.76%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 396 (0.25%)
    3 / 408 (0.74%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Erysipelas
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Neutropenic sepsis
         subjects affected / exposed
    2 / 396 (0.51%)
    0 / 408 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Respiratory tract infection
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 396 (0.25%)
    1 / 408 (0.25%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Urosepsis
         subjects affected / exposed
    0 / 396 (0.00%)
    2 / 408 (0.49%)
    0 / 50 (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
    Viral infection
         subjects affected / exposed
    2 / 396 (0.51%)
    0 / 408 (0.00%)
    0 / 50 (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
    Acute sinusitis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Anal abscess
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Breast cellulitis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 infection
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Coccidioidomycosis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Diarrhoea infectious
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Gastrointestinal infection
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    H1N1 influenza
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Infection
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Onychomycosis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Oral candidiasis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Osteomyelitis chronic
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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 staphylococcal
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Postoperative wound infection
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Pyelonephritis acute
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Rash pustular
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Sepsis syndrome
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Skin infection
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Soft tissue infection
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Wound infection
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Cellulitis gangrenous
         subjects affected / exposed
    0 / 396 (0.00%)
    0 / 408 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 396 (0.00%)
    0 / 408 (0.00%)
    1 / 50 (2.00%)
         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 device infection
         subjects affected / exposed
    1 / 396 (0.25%)
    2 / 408 (0.49%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute hepatitis B
         subjects affected / exposed
    0 / 396 (0.00%)
    0 / 408 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 396 (0.00%)
    0 / 408 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Groin abscess
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 396 (0.51%)
    1 / 408 (0.25%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Diabetes mellitus
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 408 (0.00%)
    0 / 50 (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
    Fluid retention
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 408 (0.25%)
    0 / 50 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    386 / 396 (97.47%)
    400 / 408 (98.04%)
    45 / 50 (90.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    31 / 396 (7.83%)
    53 / 408 (12.99%)
    4 / 50 (8.00%)
         occurrences all number
    93
    83
    4
    Hot flush
         subjects affected / exposed
    21 / 396 (5.30%)
    23 / 408 (5.64%)
    0 / 50 (0.00%)
         occurrences all number
    39
    26
    0
    Lymphoedema
         subjects affected / exposed
    16 / 396 (4.04%)
    24 / 408 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    18
    25
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    148 / 396 (37.37%)
    156 / 408 (38.24%)
    5 / 50 (10.00%)
         occurrences all number
    291
    320
    16
    Asthenia
         subjects affected / exposed
    122 / 396 (30.81%)
    114 / 408 (27.94%)
    3 / 50 (6.00%)
         occurrences all number
    268
    265
    3
    Oedema peripheral
         subjects affected / exposed
    111 / 396 (28.03%)
    102 / 408 (25.00%)
    1 / 50 (2.00%)
         occurrences all number
    163
    141
    1
    Mucosal inflammation
         subjects affected / exposed
    78 / 396 (19.70%)
    111 / 408 (27.21%)
    1 / 50 (2.00%)
         occurrences all number
    111
    185
    1
    Pyrexia
         subjects affected / exposed
    72 / 396 (18.18%)
    81 / 408 (19.85%)
    3 / 50 (6.00%)
         occurrences all number
    94
    138
    6
    Oedema
         subjects affected / exposed
    49 / 396 (12.37%)
    49 / 408 (12.01%)
    1 / 50 (2.00%)
         occurrences all number
    76
    84
    2
    Chills
         subjects affected / exposed
    15 / 396 (3.79%)
    34 / 408 (8.33%)
    1 / 50 (2.00%)
         occurrences all number
    18
    36
    7
    Chest pain
         subjects affected / exposed
    21 / 396 (5.30%)
    15 / 408 (3.68%)
    0 / 50 (0.00%)
         occurrences all number
    24
    17
    0
    Influenza like illness
         subjects affected / exposed
    10 / 396 (2.53%)
    23 / 408 (5.64%)
    2 / 50 (4.00%)
         occurrences all number
    12
    41
    2
    Pain
         subjects affected / exposed
    22 / 396 (5.56%)
    26 / 408 (6.37%)
    0 / 50 (0.00%)
         occurrences all number
    26
    31
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    21 / 396 (5.30%)
    28 / 408 (6.86%)
    1 / 50 (2.00%)
         occurrences all number
    29
    33
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    79 / 396 (19.95%)
    101 / 408 (24.75%)
    6 / 50 (12.00%)
         occurrences all number
    118
    146
    10
    Dyspnoea
         subjects affected / exposed
    62 / 396 (15.66%)
    67 / 408 (16.42%)
    1 / 50 (2.00%)
         occurrences all number
    87
    99
    2
    Epistaxis
         subjects affected / exposed
    35 / 396 (8.84%)
    41 / 408 (10.05%)
    2 / 50 (4.00%)
         occurrences all number
    47
    56
    4
    Oropharyngeal pain
         subjects affected / exposed
    27 / 396 (6.82%)
    32 / 408 (7.84%)
    1 / 50 (2.00%)
         occurrences all number
    32
    55
    1
    Rhinorrhoea
         subjects affected / exposed
    23 / 396 (5.81%)
    33 / 408 (8.09%)
    3 / 50 (6.00%)
         occurrences all number
    29
    43
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    55 / 396 (13.89%)
    67 / 408 (16.42%)
    2 / 50 (4.00%)
         occurrences all number
    72
    95
    3
    Depression
         subjects affected / exposed
    20 / 396 (5.05%)
    26 / 408 (6.37%)
    2 / 50 (4.00%)
         occurrences all number
    22
    33
    2
    Anxiety
         subjects affected / exposed
    20 / 396 (5.05%)
    20 / 408 (4.90%)
    1 / 50 (2.00%)
         occurrences all number
    28
    25
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    19 / 396 (4.80%)
    37 / 408 (9.07%)
    3 / 50 (6.00%)
         occurrences all number
    22
    51
    3
    Weight increased
         subjects affected / exposed
    22 / 396 (5.56%)
    17 / 408 (4.17%)
    0 / 50 (0.00%)
         occurrences all number
    35
    21
    0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    27 / 396 (6.82%)
    27 / 408 (6.62%)
    3 / 50 (6.00%)
         occurrences all number
    33
    43
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    76 / 396 (19.19%)
    106 / 408 (25.98%)
    7 / 50 (14.00%)
         occurrences all number
    128
    187
    9
    Neuropathy peripheral
         subjects affected / exposed
    79 / 396 (19.95%)
    95 / 408 (23.28%)
    1 / 50 (2.00%)
         occurrences all number
    114
    138
    1
    Dysgeusia
         subjects affected / exposed
    62 / 396 (15.66%)
    75 / 408 (18.38%)
    1 / 50 (2.00%)
         occurrences all number
    116
    95
    30
    Dizziness
         subjects affected / exposed
    53 / 396 (13.38%)
    67 / 408 (16.42%)
    4 / 50 (8.00%)
         occurrences all number
    73
    133
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    59 / 396 (14.90%)
    52 / 408 (12.75%)
    2 / 50 (4.00%)
         occurrences all number
    82
    93
    2
    Paraesthesia
         subjects affected / exposed
    41 / 396 (10.35%)
    43 / 408 (10.54%)
    0 / 50 (0.00%)
         occurrences all number
    60
    52
    0
    Hypoaesthesia
         subjects affected / exposed
    11 / 396 (2.78%)
    21 / 408 (5.15%)
    1 / 50 (2.00%)
         occurrences all number
    15
    28
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    191 / 396 (48.23%)
    209 / 408 (51.23%)
    1 / 50 (2.00%)
         occurrences all number
    797
    849
    1
    Anaemia
         subjects affected / exposed
    77 / 396 (19.44%)
    100 / 408 (24.51%)
    6 / 50 (12.00%)
         occurrences all number
    143
    151
    15
    Leukopenia
         subjects affected / exposed
    82 / 396 (20.71%)
    75 / 408 (18.38%)
    0 / 50 (0.00%)
         occurrences all number
    344
    288
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    55 / 396 (13.89%)
    60 / 408 (14.71%)
    0 / 50 (0.00%)
         occurrences all number
    63
    74
    0
    Dry eye
         subjects affected / exposed
    8 / 396 (2.02%)
    24 / 408 (5.88%)
    2 / 50 (4.00%)
         occurrences all number
    8
    27
    2
    Cataract
         subjects affected / exposed
    1 / 396 (0.25%)
    7 / 408 (1.72%)
    3 / 50 (6.00%)
         occurrences all number
    1
    8
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    191 / 396 (48.23%)
    277 / 408 (67.89%)
    25 / 50 (50.00%)
         occurrences all number
    428
    989
    155
    Nausea
         subjects affected / exposed
    168 / 396 (42.42%)
    184 / 408 (45.10%)
    4 / 50 (8.00%)
         occurrences all number
    359
    394
    7
    Vomiting
         subjects affected / exposed
    96 / 396 (24.24%)
    110 / 408 (26.96%)
    5 / 50 (10.00%)
         occurrences all number
    150
    184
    7
    Constipation
         subjects affected / exposed
    100 / 396 (25.25%)
    69 / 408 (16.91%)
    4 / 50 (8.00%)
         occurrences all number
    179
    135
    6
    Stomatitis
         subjects affected / exposed
    63 / 396 (15.91%)
    82 / 408 (20.10%)
    6 / 50 (12.00%)
         occurrences all number
    138
    167
    13
    Abdominal pain
         subjects affected / exposed
    50 / 396 (12.63%)
    64 / 408 (15.69%)
    2 / 50 (4.00%)
         occurrences all number
    66
    86
    2
    Dyspepsia
         subjects affected / exposed
    48 / 396 (12.12%)
    55 / 408 (13.48%)
    3 / 50 (6.00%)
         occurrences all number
    73
    80
    8
    Abdominal pain upper
         subjects affected / exposed
    43 / 396 (10.86%)
    44 / 408 (10.78%)
    2 / 50 (4.00%)
         occurrences all number
    54
    69
    2
    Gastritis
         subjects affected / exposed
    7 / 396 (1.77%)
    16 / 408 (3.92%)
    3 / 50 (6.00%)
         occurrences all number
    8
    20
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    240 / 396 (60.61%)
    248 / 408 (60.78%)
    4 / 50 (8.00%)
         occurrences all number
    256
    264
    5
    Rash
         subjects affected / exposed
    96 / 396 (24.24%)
    156 / 408 (38.24%)
    11 / 50 (22.00%)
         occurrences all number
    185
    288
    19
    Nail disorder
         subjects affected / exposed
    92 / 396 (23.23%)
    96 / 408 (23.53%)
    2 / 50 (4.00%)
         occurrences all number
    105
    106
    2
    Pruritus
         subjects affected / exposed
    40 / 396 (10.10%)
    75 / 408 (18.38%)
    6 / 50 (12.00%)
         occurrences all number
    67
    117
    6
    Dry skin
         subjects affected / exposed
    25 / 396 (6.31%)
    47 / 408 (11.52%)
    4 / 50 (8.00%)
         occurrences all number
    26
    53
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    22 / 396 (5.56%)
    28 / 408 (6.86%)
    1 / 50 (2.00%)
         occurrences all number
    25
    38
    1
    Erythema
         subjects affected / exposed
    20 / 396 (5.05%)
    23 / 408 (5.64%)
    1 / 50 (2.00%)
         occurrences all number
    27
    28
    1
    Eczema
         subjects affected / exposed
    5 / 396 (1.26%)
    5 / 408 (1.23%)
    3 / 50 (6.00%)
         occurrences all number
    6
    5
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    11 / 396 (2.78%)
    23 / 408 (5.64%)
    0 / 50 (0.00%)
         occurrences all number
    12
    27
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    98 / 396 (24.75%)
    97 / 408 (23.77%)
    5 / 50 (10.00%)
         occurrences all number
    209
    202
    30
    Arthralgia
         subjects affected / exposed
    71 / 396 (17.93%)
    83 / 408 (20.34%)
    5 / 50 (10.00%)
         occurrences all number
    130
    133
    5
    Pain in extremity
         subjects affected / exposed
    52 / 396 (13.13%)
    76 / 408 (18.63%)
    5 / 50 (10.00%)
         occurrences all number
    79
    116
    6
    Back pain
         subjects affected / exposed
    48 / 396 (12.12%)
    66 / 408 (16.18%)
    6 / 50 (12.00%)
         occurrences all number
    58
    98
    17
    Musculoskeletal pain
         subjects affected / exposed
    38 / 396 (9.60%)
    40 / 408 (9.80%)
    2 / 50 (4.00%)
         occurrences all number
    57
    51
    2
    Bone pain
         subjects affected / exposed
    31 / 396 (7.83%)
    37 / 408 (9.07%)
    1 / 50 (2.00%)
         occurrences all number
    56
    48
    1
    Muscle spasms
         subjects affected / exposed
    20 / 396 (5.05%)
    50 / 408 (12.25%)
    3 / 50 (6.00%)
         occurrences all number
    24
    94
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    17 / 396 (4.29%)
    22 / 408 (5.39%)
    1 / 50 (2.00%)
         occurrences all number
    22
    27
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    57 / 396 (14.39%)
    90 / 408 (22.06%)
    13 / 50 (26.00%)
         occurrences all number
    99
    174
    32
    Nasopharyngitis
         subjects affected / exposed
    60 / 396 (15.15%)
    76 / 408 (18.63%)
    13 / 50 (26.00%)
         occurrences all number
    108
    161
    58
    Urinary tract infection
         subjects affected / exposed
    29 / 396 (7.32%)
    39 / 408 (9.56%)
    4 / 50 (8.00%)
         occurrences all number
    39
    65
    6
    Influenza
         subjects affected / exposed
    22 / 396 (5.56%)
    30 / 408 (7.35%)
    6 / 50 (12.00%)
         occurrences all number
    33
    43
    10
    Paronychia
         subjects affected / exposed
    16 / 396 (4.04%)
    32 / 408 (7.84%)
    6 / 50 (12.00%)
         occurrences all number
    23
    45
    8
    Rhinitis
         subjects affected / exposed
    22 / 396 (5.56%)
    22 / 408 (5.39%)
    4 / 50 (8.00%)
         occurrences all number
    35
    50
    13
    Conjunctivitis
         subjects affected / exposed
    19 / 396 (4.80%)
    31 / 408 (7.60%)
    2 / 50 (4.00%)
         occurrences all number
    22
    45
    2
    Pharyngitis
         subjects affected / exposed
    9 / 396 (2.27%)
    22 / 408 (5.39%)
    3 / 50 (6.00%)
         occurrences all number
    10
    28
    6
    Bronchitis
         subjects affected / exposed
    15 / 396 (3.79%)
    16 / 408 (3.92%)
    4 / 50 (8.00%)
         occurrences all number
    19
    29
    5
    Cellulitis
         subjects affected / exposed
    12 / 396 (3.03%)
    16 / 408 (3.92%)
    3 / 50 (6.00%)
         occurrences all number
    14
    20
    6
    Cystitis
         subjects affected / exposed
    6 / 396 (1.52%)
    16 / 408 (3.92%)
    5 / 50 (10.00%)
         occurrences all number
    7
    25
    6
    Pneumonia
         subjects affected / exposed
    8 / 396 (2.02%)
    12 / 408 (2.94%)
    4 / 50 (8.00%)
         occurrences all number
    8
    20
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    106 / 396 (26.77%)
    120 / 408 (29.41%)
    2 / 50 (4.00%)
         occurrences all number
    176
    229
    3
    Hypokalaemia
         subjects affected / exposed
    21 / 396 (5.30%)
    37 / 408 (9.07%)
    3 / 50 (6.00%)
         occurrences all number
    28
    60
    3
    Hyperglycaemia
         subjects affected / exposed
    11 / 396 (2.78%)
    17 / 408 (4.17%)
    3 / 50 (6.00%)
         occurrences all number
    24
    19
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2007
    Protocol Amendment Version B key elements: - Modified inclusion criterion 4 to include the collection of historic left ventricular ejection fraction (LVEF) values - Added LVEF assessments during follow-up to allow long-term follow-up of cardiac function - Aligned the reporting and grading of symptomatic left ventricular dysfunction (LVSD) with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0 - Increased surveillance of anti-pertuzumab antibodies - Updated statistical analysis plan in relation to objective response, and statistical considerations and the analytical plan were further clarified - Added a hematology test on Day 8 of each treatment cycle during chemotherapy - Described with more accuracy the tumor assessment scans required at baseline
    23 Jun 2009
    Protocol Amendment Version C key elements: - Updated definition of postmenopausal women and the contraceptive requirements for women of childbearing potential, male participants with partners of childbearing potential, and pregnant partners to align with Medicines and Health Care Products Regulatory Agency (MHRA) recommendations, in accordance with the International Conference on Harmonization (ICH) M3 guideline - Added pregnancy testing requirements after discontinuation of study treatment - Clarified eligibility for enrollment into the study for participants with bone-only metastases - Clarified prior hormonal therapy in the metastatic breast cancer (MBC) setting and exclusion criterion 6 was amended to allow enrollment of participants with a history of squamous cell carcinoma - Clarified non-eligibility for participants in other interventional and non-interventional studies - Added clarification to exclusion criterion 14 regarding acceptable transaminases and alkaline phosphatase levels for inclusion into the study - Updated the schedule of assessments, deleting unnecessary assessments and correcting time points at which an assessment was required - Clarified use of positron emission tomography/computed tomography (PET/CT) scans when bone scans could not performed due to isotope shortages - Clarified the administration and discontinuation of docetaxel - Clarified the follow-up period for LVEF assessments following discontinuation of study treatment
    26 Aug 2011
    Protocol Amendment Version D key elements: - Continuation of tumor assessments until investigator-determined PD (instead of IRF-determined PD) or until 15 April 2012 (with the exception of sites in Japan) - Continuation of sites in Japan to perform tumor assessments until IRF-determined disease progression and send tumor assessment data to the IRF until notified by the Study Management Team - Maintained the study blinding procedures to reduce the chances of bias or crossover occurring after disease progression - Updated timelines for the quality-of-life assessment (FACT-B questionnaire), sampling for antibodies to pertuzumab, and Eastern Cooperative Oncology Group (ECOG) performance status assessments - Eliminated sampling for shed HER2 extracellular domain (ECD) and HER ligands
    04 May 2012
    Protocol Amendment Version E key elements: - Inserted information relating to the second interim OS analysis as requested by regulatory authorities - Added an open-label pertuzumab crossover treatment group offered to participants in the placebo treatment group who had not experienced disease progression and were still receiving study treatment. The addition of the open-label pertuzumab crossover treatment group was subject to the results of the second interim OS analysis and was allowed because a statistical significance was achieved at the second interim OS analysis. - Added a change in serious adverse event (SAE) reporting that all SAEs should be reported to the Sponsor within 24 hours of the investigator becoming aware of the event to comply with European regulations
    10 Jul 2014
    Protocol Amendment Version F key elements: -Removed study-related assessments and procedures that will not be used for any future analyses for those subjects who continue to receive study drug treatment or who are participating in the survival follow up phase of the study; -To continue to monitor the safety of subjects still receiving study treatment; -Increased the duration of required contraceptive use and the prohibition of breastfeeding to 7 months after receipt of the final dose of all study drugs, to be consistent with the revised pharmacokinetic (PK) findings for trastuzumab; -Collect long term safety data regarding pertuzumab and trastuzumab use; -Enable further analyses of safety and survival

    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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