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    Clinical Trial Results:
    Multicenter Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC-T) With Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (Herceptin®) (AC-TH) and With Docetaxel, Carboplatin and Trastuzumab (TCH) in the Adjuvant Treatment of Node Positive and High Risk Node Negative Patients With Operable Breast Cancer Containing the HER2 Alteration

    Summary
    EudraCT number
    		 2008-005127-29
    Trial protocol
    		 HU   SK  
    Global end of trial date
    30 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jul 2016
    First version publication date
    02 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TAX_GMA_302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00021255
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    17 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare disease-free survival after treatment with doxorubicin and cyclophosphamide followed by docetaxel (Taxotere®) (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (Herceptin®) (AC-TH) and with docetaxel in combination with carboplatin and Herceptin® (TCH) in the adjuvant treatment of node positive and high risk node negative subjects with operable breast cancer containing the human epidermal growth factor receptor 2 (HER2) alteration.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2001
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hong Kong: 18
    Country: Number of subjects enrolled
    India: 18
    Country: Number of subjects enrolled
    Korea, Republic of: 64
    Country: Number of subjects enrolled
    Taiwan: 57
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 68
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 3
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Croatia: 41
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Estonia: 11
    Country: Number of subjects enrolled
    France: 129
    Country: Number of subjects enrolled
    Germany: 313
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Ireland: 129
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Poland: 260
    Country: Number of subjects enrolled
    Romania: 35
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Slovakia: 20
    Country: Number of subjects enrolled
    Slovenia: 22
    Country: Number of subjects enrolled
    Spain: 90
    Country: Number of subjects enrolled
    Sweden: 29
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Cyprus: 3
    Country: Number of subjects enrolled
    Egypt: 17
    Country: Number of subjects enrolled
    Israel: 61
    Country: Number of subjects enrolled
    Lebanon: 42
    Country: Number of subjects enrolled
    Tunisia: 4
    Country: Number of subjects enrolled
    Canada: 143
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    United States: 990
    Country: Number of subjects enrolled
    Australia: 293
    Country: Number of subjects enrolled
    New Zealand: 32
    Country: Number of subjects enrolled
    South Africa: 49
    Country: Number of subjects enrolled
    Argentina: 23
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Uruguay: 7
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 4
    Worldwide total number of subjects
    3222
    EEA total number of subjects
    1315
    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)
    3028
    From 65 to 84 years
    194
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 433 centers in 43 countries. A total of 3222 subjects were randomized between 05 April 2001 and 30 March 2004.

    Pre-assignment
    Screening details
    		 Subjects were stratified according to institution, nodal status (negative, positive 1-3 nodes, positive 4 or more nodes), hormonal receptor status (estrogen and/or progesterone receptor positive versus negative) and randomized in 1:1:1 ratio to receive adjuvant therapy with either AC→ T, AC→ TH or TCH.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
    Arm description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 60 mg/m² over 5-15 minutes by intravenous (IV) bolus injection every 3 weeks.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 600 mg/m² over 5-60 minutes by IV bolus injection every 3 weeks.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere®
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 100 mg/m² over 1 hour by IV infusion every 3 weeks.

    Arm title
    		 AC Followed by Docetaxel + Herceptin (AC→TH)
    Arm description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 60 mg/m²over 5-15 minutes by IV bolus injection every 3 weeks.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 600 mg/m² over 5-60 minutes by IV bolus injection every 3 weeks.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere®
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 100 mg/m² over 1 hour by IV infusion on day 2 for the first cycle and on day 1 for all subsequent cycles.

    Investigational medicinal product name
    Herceptin®
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin 4 mg/kg by IV infusion over 90 minutes on Day 1 followed by Herceptin 2 mg/kg by IV infusion over 30 minutes on Day 8 and 15 respectively. After completion of the last cycle, subjects received Herceptin 6 mg/kg over 30 minutes by IV infusion every 3 weeks until 1 year from date of initial Herceptin dose.

    Arm title
    		 Docetaxel + Carboplatin + Herceptin (TCH)
    Arm description
    		 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Herceptin®
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin 4 mg/kg by IV infusion over 90 minutes on Day 1 and 2 mg/kg by IV infusion over 30 minutes on Day 8 and 15 respectively for first cycle. Herceptin 2 mg/kg by IV infusion over 30 minutes on Day1, 8 and 15 for all subsequent cycles. After completion of the last cycle, Herceptin 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks until 1 year from date of initial Herceptin dose.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere®
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m² by IV infusion over 1 hour on Day 2 for the first cycle and on Day 1 for all subsequent cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin at target AUC = 6 mg/mL/min by IV infusion over 30-60 minutes on Day 2 for the first cycle and on Day 1 for all subsequent cycles.

    Number of subjects in period 1
    		Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
    Started
    1073
    1074
    1075
    Treated
    1045
    1072
    1057
    Completed
    952
    804
    926
    Not completed
    121
    270
    149
         Other than specified above
    -
    38
    19
         Second primary malignancy
    -
    4
    1
         Herceptin toxicity
    -
    22
    6
         Adverse Event
    46
    30
    18
         Randomized but not treated
    28
    2
    18
         Death
    1
    -
    2
         Breast cancer relapse
    5
    18
    11
         Lost to Follow-up
    -
    2
    3
         Withdrawal by Subject
    41
    64
    26
         Protocol Violation
    -
    2
    -
         Cardiac toxicity
    -
    61
    32
         Missing
    -
    27
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
    Reporting group description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.

    Reporting group title
    AC Followed by Docetaxel + Herceptin (AC→TH)
    Reporting group description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.

    Reporting group title
    Docetaxel + Carboplatin + Herceptin (TCH)
    Reporting group description
    		 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.

    Reporting group values
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH) Total
    Number of subjects
    		 1073 1074 1075 3222
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.8 ± 9.7 48.7 ± 9.7 48.6 ± 9.9 -
    Gender categorical
    Units: Subjects
        Female
    		 1073 1074 1075 3222
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
    Reporting group description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.

    Reporting group title
    AC Followed by Docetaxel + Herceptin (AC→TH)
    Reporting group description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.

    Reporting group title
    Docetaxel + Carboplatin + Herceptin (TCH)
    Reporting group description
    		 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.

    Primary: Percentage of Subjects With Disease Free Survival at 5 Years

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    End point title
    		 Percentage of Subjects With Disease Free Survival at 5 Years [1]
    End point description
    Disease Free Survival was defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause whichever occured first. Disease free survival was estimated using the Kaplan-Meier method. Analysis was performed on Intent-To-Treat (ITT) population that included all randomized subjects.
    End point type
    Primary
    End point timeframe
    From randomization until relapse or death or up to 5 years.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analyses were performed: “Kaplan-Meier analysis, including landmark estimates of 1- to 10-year survival probabilities, median times and graph was performed”.
    End point values
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
    Number of subjects analysed
    1073
    1074
    1074
    Units: Percentage of Subjects
        number (confidence interval 95%)
    75.5 (72.8 to 78.2)
    83.2 (80.9 to 85.4)
    81 (78.6 to 83.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Free Survival at 10 Years

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    End point title
    		 Percentage of Subjects With Disease Free Survival at 10 Years
    End point description
    Disease free survival was defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause whichever occured first. Disease free survival was estimated using the Kaplan-Meier method. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization until relapse or death or up to 10 years.
    End point values
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
    Number of subjects analysed
    1073
    1074
    1075
    Units: Percentage of Subjects
        number (confidence interval 95%)
    67.2 (64.2 to 70.2)
    73.4 (70.6 to 76.2)
    72.3 (69.4 to 75.1)
    No statistical analyses for this end point

    Secondary: Overall Survival- Percentage of Subjects who Survived at 10 Years

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    End point title
    		 Overall Survival- Percentage of Subjects who Survived at 10 Years
    End point description
    Overall survival of the subjects was measured from the date of randomization up to the date of death due to any cause. Overall survival was estimated using the Kaplan-Meier method. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization until death or up to 10 years
    End point values
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
    Number of subjects analysed
    1073
    1074
    1075
    Units: Percentage of Subjects
        number (confidence interval 95%)
    78.9 (76.2 to 81.5)
    86 (83.8 to 88.2)
    83.4 (81 to 85.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from the time the subject started treatment with study drug until 30 days after the last infusion of study treatment (chemotherapy or Herceptin)
    Adverse event reporting additional description
    Reported AEs & deaths are treatment-emergent that is AEs that developed/worsened & deaths that occurred during 'on treatment period' (from first infusion of study drug until 30 days after last infusion of study drug). Safety population included all treated subjects. Source vocabulary used to define AE term: Pooled NCI-CTC v 2.0 and COSTART v 5.0
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI V2/COSTART V5
    Dictionary version
    2/5
    Reporting groups
    Reporting group title
    Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
    Reporting group description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.

    Reporting group title
    Docetaxel + Carboplatin + Herceptin (TCH)
    Reporting group description
    		 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.

    Reporting group title
    AC Followed by Docetaxel + Herceptin (AC→TH)
    Reporting group description
    		 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.

    Serious adverse events
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) Docetaxel + Carboplatin + Herceptin (TCH) AC Followed by Docetaxel + Herceptin (AC→TH)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    218 / 1018 (21.41%)
    283 / 1056 (26.80%)
    298 / 1100 (27.09%)
         number of deaths (all causes)
    194
    163
    148
         number of deaths resulting from adverse events
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Stenosis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Arrhythmia
         subjects affected / exposed
    2 / 1018 (0.20%)
    3 / 1056 (0.28%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial Anomaly
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Av Block
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Cardiomyopathy
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular Disorder
         subjects affected / exposed
    2 / 1018 (0.20%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Carotid Occlusion
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep Thrombophlebitis
         subjects affected / exposed
    6 / 1018 (0.59%)
    15 / 1056 (1.42%)
    13 / 1100 (1.18%)
         occurrences causally related to treatment / all
    4 / 9
    5 / 19
    2 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram Abnormal
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Heart Arrest
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    Heart Failure
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage
         subjects affected / exposed
    0 / 1018 (0.00%)
    2 / 1056 (0.19%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Hypotension
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left Heart Failure
         subjects affected / exposed
    8 / 1018 (0.79%)
    2 / 1056 (0.19%)
    25 / 1100 (2.27%)
         occurrences causally related to treatment / all
    1 / 10
    2 / 3
    6 / 39
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial Ischemia
         subjects affected / exposed
    0 / 1018 (0.00%)
    4 / 1056 (0.38%)
    5 / 1100 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Palpitation
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Phlebitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postural Hypotension
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    4 / 1100 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Tachycardia
         subjects affected / exposed
    2 / 1018 (0.20%)
    2 / 1056 (0.19%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Anxiety
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Infarct
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Confusion
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Depression
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    5 / 1100 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emotional Lability
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand Mal Convulsion
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Neuropathy
         subjects affected / exposed
    3 / 1018 (0.29%)
    4 / 1056 (0.38%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Vertigo
         subjects affected / exposed
    0 / 1018 (0.00%)
    2 / 1056 (0.19%)
    0 / 1100 (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
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 1018 (0.10%)
    9 / 1056 (0.85%)
    8 / 1100 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 11
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    21 / 1018 (2.06%)
    20 / 1056 (1.89%)
    23 / 1100 (2.09%)
         occurrences causally related to treatment / all
    24 / 24
    19 / 22
    27 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphedema
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 1018 (0.10%)
    2 / 1056 (0.19%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Abdominal Pain
         subjects affected / exposed
    2 / 1018 (0.20%)
    2 / 1056 (0.19%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Accidental Injury
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Aggravation Reaction
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Allergic Reaction
         subjects affected / exposed
    2 / 1018 (0.20%)
    5 / 1056 (0.47%)
    7 / 1100 (0.64%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 5
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    4 / 1018 (0.39%)
    6 / 1056 (0.57%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    4 / 4
    7 / 7
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    7 / 1018 (0.69%)
    11 / 1056 (1.04%)
    7 / 1100 (0.64%)
         occurrences causally related to treatment / all
    5 / 9
    4 / 13
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    5 / 1018 (0.49%)
    6 / 1056 (0.57%)
    7 / 1100 (0.64%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 7
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Cyst
         subjects affected / exposed
    0 / 1018 (0.00%)
    4 / 1056 (0.38%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    85 / 1018 (8.35%)
    86 / 1056 (8.14%)
    109 / 1100 (9.91%)
         occurrences causally related to treatment / all
    93 / 94
    88 / 93
    120 / 124
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune System Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    68 / 1018 (6.68%)
    85 / 1056 (8.05%)
    85 / 1100 (7.73%)
         occurrences causally related to treatment / all
    57 / 82
    64 / 99
    73 / 107
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    Injection Site Pain
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Mucous Membrane Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Pain
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Photosensitivity Reaction
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation Injury
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reaction Unevaluable
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Deafness
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear Pain
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Otitis Media
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Cholecystitis
         subjects affected / exposed
    2 / 1018 (0.20%)
    1 / 1056 (0.09%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    4 / 1056 (0.38%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Diarrhea
         subjects affected / exposed
    2 / 1018 (0.20%)
    11 / 1056 (1.04%)
    10 / 1100 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
    13 / 13
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Esophagitis
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Gastritis
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1018 (0.10%)
    3 / 1056 (0.28%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Hemorrhage
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Hematemesis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Melena
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 1018 (0.29%)
    3 / 1056 (0.28%)
    7 / 1100 (0.64%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 5
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perforated Stomach Ulcer
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Rectal Hemorrhage
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Stomach Ulcer
         subjects affected / exposed
    0 / 1018 (0.00%)
    2 / 1056 (0.19%)
    0 / 1100 (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
    Stomatitis
         subjects affected / exposed
    7 / 1018 (0.69%)
    1 / 1056 (0.09%)
    4 / 1100 (0.36%)
         occurrences causally related to treatment / all
    7 / 8
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    12 / 1018 (1.18%)
    11 / 1056 (1.04%)
    16 / 1100 (1.45%)
         occurrences causally related to treatment / all
    15 / 17
    13 / 15
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnea
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Asthma
         subjects affected / exposed
    0 / 1018 (0.00%)
    2 / 1056 (0.19%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bronchiectasis
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Edema
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Fibrosis
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 1018 (0.10%)
    2 / 1056 (0.19%)
    0 / 1100 (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
    Pleural Effusion
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Pneumonia
         subjects affected / exposed
    4 / 1018 (0.39%)
    3 / 1056 (0.28%)
    4 / 1100 (0.36%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 3
    1 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    3 / 1100 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Application Site Reaction
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exfoliative Dermatitis
         subjects affected / exposed
    3 / 1018 (0.29%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal Dermatitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Maculopapular Rash
         subjects affected / exposed
    4 / 1018 (0.39%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nail Disorder
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Benign Neoplasm
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Breast Neoplasm
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial Carcinoma
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial Disorder
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (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
    Hematuria
         subjects affected / exposed
    0 / 1018 (0.00%)
    2 / 1056 (0.19%)
    0 / 1100 (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
    Kidney Failure
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Kidney Function Abnormal
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Menstrual Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Toxic Nephropathy
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    2 / 1100 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginitis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Endocrine disorders
    Thyroid Disorder
         subjects affected / exposed
    1 / 1018 (0.10%)
    0 / 1056 (0.00%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bone Pain
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint Disorder
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Dehydration
         subjects affected / exposed
    1 / 1018 (0.10%)
    5 / 1056 (0.47%)
    5 / 1100 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Edema
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Enzymatic Abnormality
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalized Edema
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Hypokalemia
         subjects affected / exposed
    0 / 1018 (0.00%)
    2 / 1056 (0.19%)
    0 / 1100 (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
    Hypomagnesemia
         subjects affected / exposed
    0 / 1018 (0.00%)
    3 / 1056 (0.28%)
    0 / 1100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Hypovolemia
         subjects affected / exposed
    0 / 1018 (0.00%)
    1 / 1056 (0.09%)
    0 / 1100 (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
    Peripheral Edema
         subjects affected / exposed
    1 / 1018 (0.10%)
    1 / 1056 (0.09%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sgot Increased
         subjects affected / exposed
    0 / 1018 (0.00%)
    0 / 1056 (0.00%)
    1 / 1100 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         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
    		 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) Docetaxel + Carboplatin + Herceptin (TCH) AC Followed by Docetaxel + Herceptin (AC→TH)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1017 / 1018 (99.90%)
    1052 / 1056 (99.62%)
    1100 / 1100 (100.00%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    40 / 1018 (3.93%)
    78 / 1056 (7.39%)
    72 / 1100 (6.55%)
         occurrences all number
    59
    141
    124
    Left Heart Failure
         subjects affected / exposed
    30 / 1018 (2.95%)
    31 / 1056 (2.94%)
    71 / 1100 (6.45%)
         occurrences all number
    42
    53
    132
    Palpitation
         subjects affected / exposed
    69 / 1018 (6.78%)
    95 / 1056 (9.00%)
    94 / 1100 (8.55%)
         occurrences all number
    103
    164
    155
    Tachycardia
         subjects affected / exposed
    50 / 1018 (4.91%)
    67 / 1056 (6.34%)
    62 / 1100 (5.64%)
         occurrences all number
    79
    107
    101
    Nervous system disorders
    Anxiety
         subjects affected / exposed
    86 / 1018 (8.45%)
    70 / 1056 (6.63%)
    78 / 1100 (7.09%)
         occurrences all number
    134
    96
    136
    Depression
         subjects affected / exposed
    106 / 1018 (10.41%)
    119 / 1056 (11.27%)
    139 / 1100 (12.64%)
         occurrences all number
    205
    199
    256
    Dizziness
         subjects affected / exposed
    112 / 1018 (11.00%)
    130 / 1056 (12.31%)
    154 / 1100 (14.00%)
         occurrences all number
    179
    218
    226
    Dry Mouth
         subjects affected / exposed
    87 / 1018 (8.55%)
    37 / 1056 (3.50%)
    55 / 1100 (5.00%)
         occurrences all number
    163
    63
    87
    Emotional Lability
         subjects affected / exposed
    56 / 1018 (5.50%)
    41 / 1056 (3.88%)
    65 / 1100 (5.91%)
         occurrences all number
    90
    61
    110
    Insomnia
         subjects affected / exposed
    226 / 1018 (22.20%)
    252 / 1056 (23.86%)
    288 / 1100 (26.18%)
         occurrences all number
    494
    488
    556
    Neuropathy
         subjects affected / exposed
    514 / 1018 (50.49%)
    406 / 1056 (38.45%)
    569 / 1100 (51.73%)
         occurrences all number
    1294
    940
    1416
    Vasodilatation
         subjects affected / exposed
    364 / 1018 (35.76%)
    384 / 1056 (36.36%)
    416 / 1100 (37.82%)
         occurrences all number
    873
    958
    993
    Blood and lymphatic system disorders
    Lymphedema
         subjects affected / exposed
    81 / 1018 (7.96%)
    107 / 1056 (10.13%)
    94 / 1100 (8.55%)
         occurrences all number
    125
    176
    156
    General disorders and administration site conditions
    Abdominal Pain
         subjects affected / exposed
    179 / 1018 (17.58%)
    240 / 1056 (22.73%)
    220 / 1100 (20.00%)
         occurrences all number
    312
    390
    370
    Allergic Reaction
         subjects affected / exposed
    100 / 1018 (9.82%)
    153 / 1056 (14.49%)
    137 / 1100 (12.45%)
         occurrences all number
    139
    225
    192
    Asthenia
         subjects affected / exposed
    838 / 1018 (82.32%)
    878 / 1056 (83.14%)
    925 / 1100 (84.09%)
         occurrences all number
    3138
    3138
    3476
    Back Pain
         subjects affected / exposed
    82 / 1018 (8.06%)
    96 / 1056 (9.09%)
    132 / 1100 (12.00%)
         occurrences all number
    124
    149
    205
    Chest Pain
         subjects affected / exposed
    73 / 1018 (7.17%)
    91 / 1056 (8.62%)
    103 / 1100 (9.36%)
         occurrences all number
    106
    149
    163
    Chills
         subjects affected / exposed
    58 / 1018 (5.70%)
    78 / 1056 (7.39%)
    88 / 1100 (8.00%)
         occurrences all number
    81
    94
    113
    Fever
         subjects affected / exposed
    162 / 1018 (15.91%)
    145 / 1056 (13.73%)
    206 / 1100 (18.73%)
         occurrences all number
    217
    178
    282
    Headache
         subjects affected / exposed
    301 / 1018 (29.57%)
    306 / 1056 (28.98%)
    323 / 1100 (29.36%)
         occurrences all number
    622
    566
    625
    Infection
         subjects affected / exposed
    350 / 1018 (34.38%)
    327 / 1056 (30.97%)
    445 / 1100 (40.45%)
         occurrences all number
    694
    583
    852
    Injection Site Reaction
         subjects affected / exposed
    66 / 1018 (6.48%)
    84 / 1056 (7.95%)
    70 / 1100 (6.36%)
         occurrences all number
    100
    125
    108
    Pain
         subjects affected / exposed
    222 / 1018 (21.81%)
    217 / 1056 (20.55%)
    268 / 1100 (24.36%)
         occurrences all number
    394
    368
    527
    Amblyopia
         subjects affected / exposed
    34 / 1018 (3.34%)
    55 / 1056 (5.21%)
    52 / 1100 (4.73%)
         occurrences all number
    62
    95
    95
    Conjunctivitis
         subjects affected / exposed
    111 / 1018 (10.90%)
    45 / 1056 (4.26%)
    122 / 1100 (11.09%)
         occurrences all number
    221
    69
    239
    Dry Eyes
         subjects affected / exposed
    41 / 1018 (4.03%)
    30 / 1056 (2.84%)
    56 / 1100 (5.09%)
         occurrences all number
    88
    54
    98
    Lacrimation Disorder
         subjects affected / exposed
    210 / 1018 (20.63%)
    124 / 1056 (11.74%)
    264 / 1100 (24.00%)
         occurrences all number
    384
    246
    534
    Taste Perversion
         subjects affected / exposed
    291 / 1018 (28.59%)
    320 / 1056 (30.30%)
    312 / 1100 (28.36%)
         occurrences all number
    691
    738
    699
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    230 / 1018 (22.59%)
    252 / 1056 (23.86%)
    238 / 1100 (21.64%)
         occurrences all number
    486
    537
    527
    Constipation
         subjects affected / exposed
    383 / 1018 (37.62%)
    351 / 1056 (33.24%)
    403 / 1100 (36.64%)
         occurrences all number
    874
    768
    913
    Diarrhea
         subjects affected / exposed
    439 / 1018 (43.12%)
    658 / 1056 (62.31%)
    555 / 1100 (50.45%)
         occurrences all number
    926
    1568
    1268
    Dyspepsia
         subjects affected / exposed
    204 / 1018 (20.04%)
    263 / 1056 (24.91%)
    273 / 1100 (24.82%)
         occurrences all number
    398
    509
    550
    Nausea
         subjects affected / exposed
    890 / 1018 (87.43%)
    863 / 1056 (81.72%)
    967 / 1100 (87.91%)
         occurrences all number
    3242
    2880
    3405
    Stomatitis
         subjects affected / exposed
    660 / 1018 (64.83%)
    564 / 1056 (53.41%)
    735 / 1100 (66.82%)
         occurrences all number
    1847
    1252
    1959
    Vomiting
         subjects affected / exposed
    563 / 1018 (55.30%)
    428 / 1056 (40.53%)
    628 / 1100 (57.09%)
         occurrences all number
    1375
    892
    1412
    Respiratory, thoracic and mediastinal disorders
    Cough Increased
         subjects affected / exposed
    187 / 1018 (18.37%)
    147 / 1056 (13.92%)
    205 / 1100 (18.64%)
         occurrences all number
    312
    218
    361
    Dyspnea
         subjects affected / exposed
    227 / 1018 (22.30%)
    229 / 1056 (21.69%)
    270 / 1100 (24.55%)
         occurrences all number
    408
    442
    544
    Epistaxis
         subjects affected / exposed
    60 / 1018 (5.89%)
    170 / 1056 (16.10%)
    143 / 1100 (13.00%)
         occurrences all number
    85
    268
    219
    Pharyngitis
         subjects affected / exposed
    74 / 1018 (7.27%)
    60 / 1056 (5.68%)
    94 / 1100 (8.55%)
         occurrences all number
    98
    81
    135
    Rhinitis
         subjects affected / exposed
    175 / 1018 (17.19%)
    193 / 1056 (18.28%)
    277 / 1100 (25.18%)
         occurrences all number
    324
    347
    501
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1003 / 1018 (98.53%)
    1018 / 1056 (96.40%)
    1083 / 1100 (98.45%)
         occurrences all number
    2350
    2486
    2556
    Dry Skin
         subjects affected / exposed
    76 / 1018 (7.47%)
    61 / 1056 (5.78%)
    101 / 1100 (9.18%)
         occurrences all number
    148
    100
    168
    Exfoliative Dermatitis
         subjects affected / exposed
    87 / 1018 (8.55%)
    32 / 1056 (3.03%)
    87 / 1100 (7.91%)
         occurrences all number
    189
    51
    175
    Maculopapular Rash
         subjects affected / exposed
    275 / 1018 (27.01%)
    330 / 1056 (31.25%)
    354 / 1100 (32.18%)
         occurrences all number
    540
    644
    680
    Nail Disorder
         subjects affected / exposed
    507 / 1018 (49.80%)
    303 / 1056 (28.69%)
    484 / 1100 (44.00%)
         occurrences all number
    1075
    620
    1026
    Pruritus
         subjects affected / exposed
    38 / 1018 (3.73%)
    66 / 1056 (6.25%)
    50 / 1100 (4.55%)
         occurrences all number
    65
    103
    71
    Rash
         subjects affected / exposed
    238 / 1018 (23.38%)
    313 / 1056 (29.64%)
    279 / 1100 (25.36%)
         occurrences all number
    357
    526
    425
    Skin Discoloration
         subjects affected / exposed
    65 / 1018 (6.39%)
    50 / 1056 (4.73%)
    67 / 1100 (6.09%)
         occurrences all number
    124
    83
    123
    Sweating
         subjects affected / exposed
    67 / 1018 (6.58%)
    73 / 1056 (6.91%)
    67 / 1100 (6.09%)
         occurrences all number
    119
    118
    104
    Renal and urinary disorders
    Breast Pain
         subjects affected / exposed
    53 / 1018 (5.21%)
    62 / 1056 (5.87%)
    59 / 1100 (5.36%)
         occurrences all number
    80
    107
    91
    Dysuria
         subjects affected / exposed
    24 / 1018 (2.36%)
    58 / 1056 (5.49%)
    51 / 1100 (4.64%)
         occurrences all number
    32
    73
    76
    Menstrual Disorder
         subjects affected / exposed
    368 / 1018 (36.15%)
    384 / 1056 (36.36%)
    356 / 1100 (32.36%)
         occurrences all number
    827
    907
    818
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    439 / 1018 (43.12%)
    335 / 1056 (31.72%)
    515 / 1100 (46.82%)
         occurrences all number
    1003
    739
    1223
    Bone Pain
         subjects affected / exposed
    187 / 1018 (18.37%)
    144 / 1056 (13.64%)
    235 / 1100 (21.36%)
         occurrences all number
    393
    287
    475
    Myalgia
         subjects affected / exposed
    541 / 1018 (53.14%)
    415 / 1056 (39.30%)
    614 / 1100 (55.82%)
         occurrences all number
    1381
    944
    1493
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    77 / 1018 (7.56%)
    79 / 1056 (7.48%)
    85 / 1100 (7.73%)
         occurrences all number
    213
    218
    239
    Peripheral Edema
         subjects affected / exposed
    339 / 1018 (33.30%)
    347 / 1056 (32.86%)
    405 / 1100 (36.82%)
         occurrences all number
    681
    708
    862
    Weight Gain
         subjects affected / exposed
    197 / 1018 (19.35%)
    254 / 1056 (24.05%)
    262 / 1100 (23.82%)
         occurrences all number
    425
    559
    574
    Weight Loss
         subjects affected / exposed
    81 / 1018 (7.96%)
    69 / 1056 (6.53%)
    100 / 1100 (9.09%)
         occurrences all number
    164
    143
    236

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2001
    This amendment contained the following substantive changes: • Echocardiography was allowed at study entry (in addition to multiple-gated acquisition [MUGA] scans) for confirmation of a subject’s left ventricular ejection fraction (LVEF) status. • Echocardiography guidelines and availability of videotapes of echocardiograms were added. • An LVEF evaluation was added at 36 months (AC→T and AC→TH) and 37.5 months (TCH) to allow for long-term assessment of cardiac function. • Clarifications regarding the dosing of carboplatin and trastuzumab, according to a subject’s weight modification, were added.
    30 Jul 2001
    This amendment contained the following substantive changes: • The dosing schedule for trastuzumab monotherapy after completion of chemotherapy was modified from administration once a week to administration every 3 weeks based on the results of two studies of the safety, anti-tumor activity, and pharmacokinetics of trastuzumab when administered every 3 weeks to subjects with HER2-positive (by immunohistochemistry or fluorescence in situ hybridization [FISH]) metastatic breast cancer (MBC). • Guidelines for trastuzumab initiation were modified for the AC→TH arm. • The trastuzumab post-infusion observation periods were revised. • The optional HER2 extracellular domain (ECD) and cardiac biochemical marker substudies were extended.
    10 Apr 2002
    This amendment contained the following substantive changes: • The TCH regimen was modified so that the platinum salt was limited to carboplatin (ie, cisplatin was no longer allowed), based on updated results from the BCIRG 101 and 102 studies. • The instructions describing the administration of trastuzumab and the dose calculation for carboplatin was clarified. • Measurement of the follicle-stimulating hormone to luteinizing hormone ratio to assess menopausal status in subjects <55 years old with a history of hysterectomy without bilateral ovariectomy was no longer required.
    17 Mar 2005
    This amendment contained the following substantive changes: • Statistical considerations were revised as follows: − Based on the results of BCIRG 001 study, the assumed DFS rate at 5 years in the AC→T arm was changed from 55% to 70%. − The independed data monitoring committee (IDMC) requested interim efficacy analyses when 300, 450, and 650 DFS events had been observed and a main analysis when 900 DFS events had been observed (the initial protocol called for one interim analysis at 654 events and a final analysis at 1308 events). − In order to gain power for the two comparisons of main interest, a “step-down” testing procedure was proposed (instead of three pairwise comparisons). It was also proposed to use the O’Brien-Fleming spending function instead of the Haybittle-Peto. • Following a request from the IDMC, one additional cardiac safety analysis was to be conducted when all subjects had been observed for at least 9 months. • The indication for adjuvant hormonal therapy was modified to allow the use of aromatase inhibitors for postmenopausal subjects who were estrogen receptor (ER)- or progesteron receptor (PR)-positive, as well as for subjects for whom tamoxifen was contraindicated. • In addition, the use of letrozole was allowed for subjects having completed 5 years of tamoxifen therapy. • Based on American Society of Clinical Oncology 2002 follow-up guidelines, hematologic and blood chemistry evaluations and chest X-rays were no longer required during the follow-up period.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21991949
    http://www.ncbi.nlm.nih.gov/pubmed/23814044
    http://www.ncbi.nlm.nih.gov/pubmed/23420271
    http://www.ncbi.nlm.nih.gov/pubmed/21189395
    http://www.ncbi.nlm.nih.gov/pubmed/25649019
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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