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    Clinical Trial Results:
    A Randomized, Open-Label, Phase III Study of Taxane Based Chemotherapy with Lapatinib or Trastuzumab as First-Line Therapy for Women with HER2/neu Positive Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2007-004568-27
    Trial protocol
    		 DE   NL   ES   IT   BE   GB   FR  
    Global end of trial date
    27 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jun 2023
    First version publication date
    07 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    108919
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00667251
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Novartis: CLAP016A2303, NCI US - Physician Data Query: CAN-NCIC-MA31, PDQ: CDR0000594764
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    27 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the progression-free survival of taxane based chemotherapy plus lapatinib for 24 weeks followed by single agent lapatinib therapy to taxane based chemotherapy plus trastuzumab for 24 weeks followed by single agent trastuzumab therapy, in women with human epidermal growth factor receptor 2 (HER2)/neu positive breast cancer (by local or central laboratory testing) which is metastatic, and with no prior chemotherapy and/or HER2/neu targeted therapy in the metastatic setting.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Oct 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 75
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 66
    Country: Number of subjects enrolled
    India: 8
    Country: Number of subjects enrolled
    Israel: 31
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Russian Federation: 101
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    United Kingdom: 65
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Thailand: 21
    Worldwide total number of subjects
    652
    EEA total number of subjects
    169
    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)
    523
    From 65 to 84 years
    128
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted at 167 centers in 21 countries worldwide.

    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
    		 Lapatinib (LTax/L)
    Arm description
    		 Lapatinib 1250 mg once daily. Taxane based chemotherapy: Paclitaxel 80 mg/m2 IV once weekly (Days 1, 8, and 15 of a 4-week cycle) OR Docetaxel 75 mg/m2 IV once every 3 weeks (Day 1 of a 3-week cycle) plus G-CSF: according to institutional standards. Followed by Lapatinib 1500 mg once daily until disease progression.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    lapatinib ditosylate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1250 mg once daily (while given with taxane). 1500mg once daily (when given alone after taxane completion).

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV q weekly (loading dose 4mg/kg; subsequent doses 2mg/kg) or IV q 3 weekly (loading dose 8mg/kg, subsequent doses 6mg/kg).

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.

    Arm title
    		 Trastuzumab (TTax/T)
    Arm description
    		 Trastuzumab IV once weekly (loading dose 4 mg/kg, subsequent doses 2 mg/kg) and Paclitaxel 80 mg/m2 IV once weekly (Days 1, 8, and 15 of a 4-week cycle) OR Trastuzumab IV once every 3 weeks (loading dose 8 mg/kg, subsequent doses 6 mg/kg) and Docetaxel 75 mg/m2 IV once every 3 weeks (Day 1 of a 3-week cycle). Followed by Trastuzumab 6 mg/kg IV once every 3 weeks until disease progression.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).

    Number of subjects in period 1
    		Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Started
    326
    326
    Randomized not Treated
    4
    1
    Central HER2 positive
    270
    267
    Safety Population
    322
    325
    Completed
    0
    0
    Not completed
    326
    326
         Adverse event, serious fatal
    6
    11
         Disease progression
    232
    203
         Toxicity
    44
    23
         Refused further treatment (not due to toxicity)
    8
    7
         Intercurrent illness
    5
    6
         Primary reason for withdrawal = missing
    1
    1
         Subject Reached Protocol-Defined Stopping Criteria
    18
    70
         Symptomatic progression
    8
    4
         Randomized not Treated
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lapatinib (LTax/L)
    Reporting group description
    		 Lapatinib 1250 mg once daily. Taxane based chemotherapy: Paclitaxel 80 mg/m2 IV once weekly (Days 1, 8, and 15 of a 4-week cycle) OR Docetaxel 75 mg/m2 IV once every 3 weeks (Day 1 of a 3-week cycle) plus G-CSF: according to institutional standards. Followed by Lapatinib 1500 mg once daily until disease progression.

    Reporting group title
    Trastuzumab (TTax/T)
    Reporting group description
    		 Trastuzumab IV once weekly (loading dose 4 mg/kg, subsequent doses 2 mg/kg) and Paclitaxel 80 mg/m2 IV once weekly (Days 1, 8, and 15 of a 4-week cycle) OR Trastuzumab IV once every 3 weeks (loading dose 8 mg/kg, subsequent doses 6 mg/kg) and Docetaxel 75 mg/m2 IV once every 3 weeks (Day 1 of a 3-week cycle). Followed by Trastuzumab 6 mg/kg IV once every 3 weeks until disease progression.

    Reporting group values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T) Total
    Number of subjects
    		 326 326 652
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 260 263 523
        >=65 years
    		 66 63 129
    Age Continuous
    Units: years
        median (full range (min-max))
    		 55.4 (26.6 to 87.1) 54.4 (29.3 to 84.3) -
    Sex: Female, Male
    Units: Participants
        Female
    		 326 326 652
        Male
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 34 34 68
        Not Hispanic or Latino
    		 288 283 571
        Unknown or Not Reported
    		 4 9 13
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 4 4 8
        Asian
    		 67 74 141
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 5 8 13
        White
    		 246 234 480
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 3 6 9
    Region of Enrollment
    Units: Subjects
        United States
    		 10 13 23
        Taiwan
    		 11 11 22
        Thailand
    		 9 12 21
        Spain
    		 19 19 38
        Ukraine
    		 4 4 8
        Russian Federation
    		 55 46 101
        Israel
    		 16 15 31
        United Kingdom
    		 33 32 65
        Italy
    		 5 8 13
        India
    		 4 4 8
        France
    		 5 5 10
        Mexico
    		 3 6 9
        Canada
    		 39 36 75
        Argentina
    		 8 4 12
        Poland
    		 7 12 19
        Belgium
    		 3 6 9
        Australia
    		 17 13 30
        Netherlands
    		 7 7 14
        Germany
    		 32 34 66
        Japan
    		 22 20 42
        Korea, Republic of
    		 17 19 36
    Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status classifies participants according to their functional impairment, and scores indicate: 0, fully active; 1, ambulatory, restricted strenuous activity; 2, ambulatory, no work activity; 3, partially confined to bed; 4, totally confined in bed; 5, death.
    Units: Subjects
        0, fully active
    		 196 204 400
        1, ambulatory, restricted strenuous activity
    		 118 112 230
        2, ambulatory, no work activity
    		 12 10 22
    Disease Status
    Units: Subjects
        Primary diagnosis
    		 138 138 276
        Progression after therapy
    		 187 187 374
        Missing
    		 1 1 2
    Central review human epidermal growth factor receptor 2 (HER2) status
    Units: Subjects
        Positive IHC or FISH
    		 270 267 537
        Equivocal IHC and FISH
    		 9 5 14
        Negative IHC and FISH
    		 36 46 82
        Unknown
    		 11 8 19
    Central review estrogen receptor (ER) status
    Units: Subjects
        Positive (>0)
    		 213 208 421
        Negative
    		 96 107 203
        Missing
    		 17 11 28
    Central review progesterone receptor (PgR) status
    Units: Subjects
        Positive (>0)
    		 116 104 220
        Negative
    		 190 204 394
        Missing
    		 20 18 38
    Central Review of Cytokeratin 5 (CK5) Status
    Units: Subjects
        Positive (>0)
    		 58 41 99
        Negative
    		 210 218 428
        Missing
    		 58 67 125
    Central Review of epidermal growth factor receptor (EGFR) Status
    Units: Subjects
        Positive (>0)
    		 71 77 148
        Negative
    		 194 181 375
        Missing
    		 61 68 129
    Prior (neo)adjuvant HER2 targeted therapy
    Units: Subjects
        Prior (neo)adjuvant HER2 targeted therapy = Yes
    		 59 59 118
        Prior (neo)adjuvant HER2 targeted therapy = No
    		 267 267 534
    Prior (neo)adjuvant taxane chemotherapy
    Units: Subjects
        Prior (neo)adjuvant taxane chemotherapy = Yes
    		 65 69 134
        Prior (neo)adjuvant taxane chemotherapy = No
    		 261 257 518
    Planned taxane treatment
    Units: Subjects
        Weekly paclitaxel
    		 146 146 292
        3-weekly docetaxel
    		 180 180 360
    Liver metastasis
    Units: Subjects
        Liver metastasis = Yes
    		 149 150 299
        Liver metastasis = No
    		 177 176 353
    Prior neoadjuvant therapy/Other chemotherapy
    Units: Subjects
        Prior neoadjuvant therapy/Other chemotherapy = Yes
    		 146 161 307
        Prior neoadjuvant therapy/Other chemotherapy = No
    		 180 165 345
    Prior neoadjuvant therapy/Anthracyclines
    Units: Subjects
        Prior neoadjuvant therapy/Anthracyclines = Yes
    		 128 140 268
        Prior neoadjuvant therapy/Anthracyclines = No
    		 198 186 384
    Prior neoadjuvant therapy/Other therapy
    Units: Subjects
        Prior neoadjuvant therapy/Other therapy = Yes
    		 5 2 7
        Prior neoadjuvant therapy/Other therapy = No
    		 321 323 644
        Prior neoadjuvant therapy/Other therapy = Missing
    		 0 1 1
    Prior neoadjuvant/Metastatic radiotherapy
    Units: Subjects
        Prior neoadjuvant/Metastatic radiotherapy = Yes
    		 138 149 287
        Prior neoadjuvant/Metastatic radiotherapy = No
    		 187 176 363
        Prior neoadjuvant/Metastatic radiotherapy= Missing
    		 1 1 2
    Prior neoadjuvant/Metastatic endocrine therapy
    Units: Subjects
        Prior nad/Metastatic endocrine therapy = Yes
    		 122 127 249
        Prior nad/Metastatic endocrine therapy = No
    		 204 198 402
        Prior nad/Metastatic endocrine therapy = Missing
    		 0 1 1
    Central Review of Antigen KI-67 (ki67)
    Units: % cells positive
        geometric mean (full range (min-max))
    		 33.33 (0 to 100) 31.43 (0 to 90) -

    End points

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    End points reporting groups
    Reporting group title
    Lapatinib (LTax/L)
    Reporting group description
    		 Lapatinib 1250 mg once daily. Taxane based chemotherapy: Paclitaxel 80 mg/m2 IV once weekly (Days 1, 8, and 15 of a 4-week cycle) OR Docetaxel 75 mg/m2 IV once every 3 weeks (Day 1 of a 3-week cycle) plus G-CSF: according to institutional standards. Followed by Lapatinib 1500 mg once daily until disease progression.

    Reporting group title
    Trastuzumab (TTax/T)
    Reporting group description
    		 Trastuzumab IV once weekly (loading dose 4 mg/kg, subsequent doses 2 mg/kg) and Paclitaxel 80 mg/m2 IV once weekly (Days 1, 8, and 15 of a 4-week cycle) OR Trastuzumab IV once every 3 weeks (loading dose 8 mg/kg, subsequent doses 6 mg/kg) and Docetaxel 75 mg/m2 IV once every 3 weeks (Day 1 of a 3-week cycle). Followed by Trastuzumab 6 mg/kg IV once every 3 weeks until disease progression.

    Subject analysis set title
    Crossed over to Trastuzumab (TTax/T) after IA results
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Crossed over to Trastuzumab (TTax/T) after IA results

    Subject analysis set title
    Overall TTax/T
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Overall TTax/T

    Subject analysis set title
    Crossed over to Trastuzumab (TTax/T) after IA results
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Crossed over to Trastuzumab (TTax/T) after IA results

    Subject analysis set title
    Overall TTax/T
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Overall TTax/T

    Subject analysis set title
    Crossed over to Trastuzumab (TTax/T) after IA results
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Crossed over to Trastuzumab (TTax/T) after Interim Analysis (IA) results

    Primary: Progression Free Survival (PFS) at the time of Primary Results

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    End point title
    		 Progression Free Survival (PFS) at the time of Primary Results
    End point description
    Progression free survival (PFS) was defined as the interval of time between the date of randomization and the earliest date of RECIST 1.0 assessment of disease progression (with radiological evidence) or death from any cause, or to the date of censor. Disease progression was based on assessments by the Investigator.
    End point type
    Primary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to approximately 39 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Months
    median (full range (min-max))
        Intent-to-Treat (ITT) population (n=326, 326)
    8.97 (0.30 to 32.69)
    11.30 (0.30 to 38.54)
        centrally-confirmed HER2+ population (n=270, 267)
    9.13 (0.30 to 32.69)
    13.63 (0.30 to 38.54)
    Statistical analysis title
    		 PFS at Primary Analysis (Central HER2+ population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.484
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.204
         upper limit
    		 1.829
    Statistical analysis title
    		 PFS at Primary Analysis (IIT population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.367
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.133
         upper limit
    		 1.648

    Secondary: Progression Free Survival (PFS) at the time of Final Analysis

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    End point title
    		 Progression Free Survival (PFS) at the time of Final Analysis
    End point description
    Progression free survival (PFS) was defined as the interval of time between the date of randomization and the earliest date of RECIST 1.0 assessment of disease progression (with radiological evidence) or death from any cause, or to the date of censor. Subjects who crossover the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at the last PFS assessment before crossover. Disease progression was based on assessments by the Investigator.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Months
    median (full range (min-max))
        Intent-to-Treat (ITT) population (n=326, 326)
    9.1 (8.5 to 10.8)
    11.5 (10.9 to 13.8)
        centrally-confirmed HER2+ population (n=270, 267)
    9.4 (8.5 to 11.0)
    13.8 (11.2 to 14.2)
    Statistical analysis title
    		 PFS at Final Analysis (Central HER2+ population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.4968
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2251
         upper limit
    		 1.8288
    Statistical analysis title
    		 PFS at Final Analysis (IIT population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3722
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1466
         upper limit
    		 1.6422

    Secondary: Overall Survival (OS) (Central HER2+ population)

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    End point title
    		 Overall Survival (OS) (Central HER2+ population)
    End point description
    Overall Survival (OS) was defined as the time interval between the date of randomization and the date of death from any cause. Subjects who were still alive at the time of the final analysis or became lost to follow-up, were censored at their last contact date. Subjects who crossover the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at last known alive date prior to crossover.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of death from any cause, assessed up approximately 165 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    270
    267
    Units: Months
        median (confidence interval 95%)
    30.0 (24.2 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Overall Survival (OS) (Central HER2+ population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.5818
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1181
         upper limit
    		 2.2379

    Secondary: Overall Survival (OS) (IIT population)

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    End point title
    		 Overall Survival (OS) (IIT population)
    End point description
    Overall Survival (OS) was defined as the time interval between the date of randomization and the date of death from any cause. Subjects who were still alive at the time of the final analysis or became lost to follow-up, were censored at their last contact date. Subjects who crossover the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at last known alive date prior to crossover.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of death from any cause, assessed up approximately 165 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Months
        median (confidence interval 95%)
    30.0 (24.2 to 999)
    38.3 (31.0 to 999)
    Statistical analysis title
    		 Overall Survival (OS) (IIT population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3786
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.0246
         upper limit
    		 1.8549

    Secondary: Incidence of Central Nervous System (CNS) metastasis at first progression (IIT population)

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    End point title
    		 Incidence of Central Nervous System (CNS) metastasis at first progression (IIT population)
    End point description
    The incidence of Central Nervous System (CNS) metastasis at first progression was defined as the ratio of the number of subjects with CNS metastasis at progression over the total number of subjects.
    End point type
    Secondary
    End point timeframe
    From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T) Crossed over to Trastuzumab (TTax/T) after IA results Overall TTax/T
    Number of subjects analysed
    326
    326
    5
    331
    Units: Participants
        CNS metastasis at first progression = Yes
    47
    55
    1
    56
        CNS metastasis at first progression = No
    155
    119
    4
    123
        CNS metastasis at first progression = Unknown
    66
    62
    0
    62
    No statistical analyses for this end point

    Secondary: Incidence of Central Nervous System (CNS) metastasis at first progression (Central HER2+ population)

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    End point title
    		 Incidence of Central Nervous System (CNS) metastasis at first progression (Central HER2+ population)
    End point description
    The incidence of Central Nervous System (CNS) metastasis at first progression was defined as the ratio of the number of subjects with CNS metastasis at progression over the total number of subjects.
    End point type
    Secondary
    End point timeframe
    From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T) Crossed over to Trastuzumab (TTax/T) after IA results Overall TTax/T
    Number of subjects analysed
    270
    267
    4
    271
    Units: Participants
        CNS metastasis at first progression = Yes
    43
    50
    1
    51
        CNS metastasis at first progression = No
    128
    92
    3
    95
        CNS metastasis at first progression = Unknown
    53
    44
    0
    44
    No statistical analyses for this end point

    Secondary: Time to Central Nervous System (CNS) metastasis (IIT population)

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    End point title
    		 Time to Central Nervous System (CNS) metastasis (IIT population)
    End point description
    Time to Central Nervous System (CNS) metastasis was defined as the time from randomization until disease progression where CNS metastasis was documented at the time of first breast cancer progression. Subjects who crossed over the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at RECIST assessment prior to crossover.
    End point type
    Secondary
    End point timeframe
    From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Months
        median (full range (min-max))
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Time to CNS metastasis (IIT population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.0916
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7271
         upper limit
    		 1.6389

    Secondary: Time to Central Nervous System (CNS) metastasis (Central HER2+ population)

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    End point title
    		 Time to Central Nervous System (CNS) metastasis (Central HER2+ population)
    End point description
    Time to Central Nervous System (CNS) metastasis was defined as the time from randomization until disease progression where CNS metastasis was documented at the time of first breast cancer progression. Subjects who crossed over the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at RECIST assessment prior to crossover.
    End point type
    Secondary
    End point timeframe
    From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    270
    267
    Units: Months
        median (full range (min-max))
    999 (25.4 to 999)
    999 (27.7 to 999)
    Statistical analysis title
    		 Time to CNS metastasis (Central HER2+ population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.0951
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7144
         upper limit
    		 1.6787

    Secondary: Overall Response Rate (ORR) (IIT population)

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    End point title
    		 Overall Response Rate (ORR) (IIT population)
    End point description
    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The ORR was calculated from the Investigator’s assessment of response based on RECIST 1.1. Subjects with an unknown or missing response were treated as non-responders; i.e. they were included in the denominator when calculating the percentages.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Percentage of Participants
        number (confidence interval 95%)
    64.2 (58.0 to 70.1)
    63.3 (57.3 to 69.1)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) (Central HER2+ population)

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    End point title
    		 Overall Response Rate (ORR) (Central HER2+ population)
    End point description
    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The ORR was calculated from the Investigator’s assessment of response based on RECIST 1.1. Subjects with an unknown or missing response were treated as non-responders; i.e. they were included in the denominator when calculating the percentages.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    270
    267
    Units: Percentage of Participants
        number (confidence interval 95%)
    66.7 (60.0 to 72.9)
    67.4 (60.8 to 73.5)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Response (CBR) (Central HER2+ population)

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    End point title
    		 Clinical Benefit Response (CBR) (Central HER2+ population)
    End point description
    Clinical Benefit Response (CBR) was defined as the percentage with evidence of Complete Response (CR), Partial Response (PR) (participants with at least 1 measurable lesion at baseline), or maintaining Stable Disease (SD) for at least 24 weeks (all subjects, with or without measurable disease at baseline) while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Participants were considered to be positive (Yes) for CBR if they experienced any CR or PR for any duration prior to progressive disease. Participants were considered to be negative (No) for CBR if they had progressive disease prior to Week 24 without prior confirmed CR or PR.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    270
    267
    Units: Percentage of Participants
        number (confidence interval 95%)
    61.1 (55.0 to 67.0)
    65.2 (59.1 to 70.9)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Response (CBR) (IIT population)

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    End point title
    		 Clinical Benefit Response (CBR) (IIT population)
    End point description
    Clinical Benefit Response (CBR) was defined as the percentage with evidence of Complete Response (CR), Partial Response (PR) (participants with at least 1 measurable lesion at baseline), or maintaining Stable Disease (SD) for at least 24 weeks (all subjects, with or without measurable disease at baseline) while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Participants were considered to be positive (Yes) for CBR if they experienced any CR or PR for any duration prior to progressive disease. Participants were considered to be negative (No) for CBR if they had progressive disease prior to Week 24 without prior confirmed CR or PR.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Percentage of Participants
        number (confidence interval 95%)
    60.4 (54.9 to 65.8)
    62.0 (56.5 to 67.3)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) (Central HER2+ population)

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    End point title
    		 Time to Response (TTR) (Central HER2+ population)
    End point description
    Time to Response was defined as the time from randomization to the earliest date of Complete Response (CR) or Partial Response (PR). The event of first response was the first CR or PR; censoring was at PD date for those who progressed or at the last RECIST date if no progression occurred.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    270
    267
    Units: Months
        median (confidence interval 95%)
    2.9 (2.8 to 3.0)
    2.9 (2.8 to 3.0)
    Statistical analysis title
    		 Time to Response (TTR) (Central HER2+ population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9573
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7544
         upper limit
    		 1.2148

    Secondary: Time to Response (TTR) (IIT population)

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    End point title
    		 Time to Response (TTR) (IIT population)
    End point description
    Time to Response was defined as the time from randomization to the earliest date of Complete Response (CR) or Partial Response (PR). The event of first response was the first CR or PR; censoring was at PD date for those who progressed or at the last RECIST date if no progression occurred.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of first response, assessed up approximately 45 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Months
        median (confidence interval 95%)
    2.9 (2.8 to 3.0)
    2.9 (2.8 to 3.0)
    Statistical analysis title
    		 Time to Response (TTR) (IIT population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.0091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.809
         upper limit
    		 1.2586

    Secondary: Duration of Response (DoR) (IIT population)

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    End point title
    		 Duration of Response (DoR) (IIT population)
    End point description
    Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented sign of Progressive Disease or Death, with censoring at the last RECIST date if no progression occurred.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 165 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    165
    171
    Units: Months
        median (confidence interval 95%)
    8.3 (7.6 to 9.4)
    11.1 (9.6 to 12.5)
    Statistical analysis title
    		 DoR (IIT population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.4866
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1479
         upper limit
    		 1.9251

    Secondary: Duration of Response (DoR) (Central HER2+ population)

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    End point title
    		 Duration of Response (DoR) (Central HER2+ population)
    End point description
    Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented sign of Progressive Disease or Death, with censoring at the last RECIST date if no progression occurred.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 165 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    144
    151
    Units: Months
        median (confidence interval 95%)
    8.3 (7.2 to 9.9)
    11.1 (10.6 to 13.8)
    Statistical analysis title
    		 DoR (Central HER2+ population)
    Comparison groups
    Lapatinib (LTax/L) v Trastuzumab (TTax/T)
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.5594
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1767
         upper limit
    		 2.0666

    Secondary: Number of Participants achieving European Quality of Life (EuroQol) – 5 Domain (EQ-5D) score (Canadian and Australian centers only)

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    End point title
    		 Number of Participants achieving European Quality of Life (EuroQol) – 5 Domain (EQ-5D) score (Canadian and Australian centers only)
    End point description
    The European Quality of Life (EuroQol) – 5 Domain (EQ-5D) self-administered questionnaire consists of two pages comprising the EQ-5D descriptive system and the EQ Visual Analogue Scale (VAS). The EQ-5D descriptive system comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and each dimension comprises three levels (no problems, some problems, extreme problems, unable to perform the activity).
    End point type
    Secondary
    End point timeframe
    Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week 120, Week 144
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Participants
        Mobility @ Week 12|No Problems
    29
    27
        Self-Care @ Week 12|No Problems
    41
    32
        Usual Activities @ Week 12|No Problems
    16
    22
        Pain/Discomfort @ Week 12|No Problems
    16
    16
        Anxiety/Depression @Week 12|No Problems
    24
    22
        Mobility @ Week 24|No Problems
    26
    20
        Self-Care @ Week 24|No Problems
    38
    31
        Usual Activities @ Week 24|No Problems
    18
    18
        Pain/Discomfort @ Week 24|No Problems
    10
    12
        Anxiety/Depression @ Week 24|No Problems
    23
    18
        Mobility @ Week 36|No Problems
    21
    26
        Self-Care @ Week 36|No Problems
    28
    30
        Usual Activities @ Week 36|No Problems
    17
    16
        Pain/Discomfort @ Week 36|No Problems
    9
    13
        Anxiety/Depression @Week 36|No Problems
    18
    18
        Mobility @ Week 48|No Problems
    14
    18
        Self-Care @ Week 48|No Problems
    18
    26
        Usual Activities @ Week 48|No Problems
    15
    16
        Pain/Discomfort @ Week 48|No Problems
    6
    12
        Anxiety/Depression @ Week 48|No Problems
    10
    20
        Mobility @ Week 60|No Problems
    8
    16
        Self-Care @ Week 60|No Problems
    8
    20
        Usual Activities @ Week 60|No Problems
    7
    12
        Pain/Discomfort @ Week 60|No Problems
    5
    11
        Anxiety/Depression @ Week 60|No Problems
    5
    12
        Mobility @ Week 72|No Problems
    7
    13
        Self-Care @ Week 72|No Problems
    8
    15
        Usual Activities @ Week 72|No Problems
    7
    8
        Pain/Discomfort @ Week 72|No Problems
    6
    9
        Anxiety/Depression @ Week 72|No Problems
    4
    8
        Mobility @ Week 84|No Problems
    5
    6
        Self-Care @ Week 84|No Problems
    6
    8
        Usual Activities @ Week 84|No Problems
    5
    5
        Pain/Discomfort @ Week 84|No Problems
    4
    2
        Anxiety/Depression @ Week 84|No Problems
    3
    4
        Mobility @ Week 96|No Problems
    5
    3
        Self-Care @ Week 96|No Problems
    5
    5
        Usual Activities @ Week 96|No Problems
    3
    3
        Pain/Discomfort @ Week 96|No Problems
    2
    1
        Anxiety/Depression @ Week 96|No Problems
    1
    3
        Mobility @ Week 120|No Problems
    4
    2
        Self-Care @ Week 120|No Problems
    4
    3
        Usual Activities @ Week 120|No Problems
    4
    2
        Pain/Discomfort @ Week 120|No Problems
    3
    2
        Anxiety/Depression @ Week 120|No Problems
    1
    3
        Mobility @ Week 144|No Problems
    1
    1
        Self-Care @ Week 144|No Problems
    1
    1
        Usual Activities @ Week 144|No Problems
    1
    1
        Pain/Discomfort @ Week 144|No Problems
    1
    1
        Anxiety/Depression @ Week 144|No Problems
    0
    1
        Mobility @ Week 12|Some problems
    16
    9
        Self-Care @ Week 12|Some problems
    4
    2
        Usual Activities @ Week 12|Some problems
    25
    13
        Pain/Discomfort @ Week 12|Some problems
    28
    20
        Anxiety/Depression @ Week 12|Some problems
    20
    14
        Mobility @ Week 24|Some problems
    14
    14
        Self-Care @ Week 24|Some problems
    3
    3
        Usual Activities @ Week 24|Some problems
    22
    14
        Pain/Discomfort @ Week 24|Some problems
    30
    21
        Anxiety/Depression @ Week 24|Some problems
    18
    15
        Mobility @ Week 36|Some problems
    10
    5
        Self-Care @ Week 36|Some problems
    2
    1
        Usual Activities @ Week 36|Some problems
    13
    14
        Pain/Discomfort @ Week 36|Some problems
    18
    16
        Anxiety/Depression @ Week 36|Some problems
    12
    13
        Mobility @ Week 48|Some problems
    4
    9
        Self-Care @ Week 48|Some problems
    0
    1
        Usual Activities @ Week 48|Some problems
    3
    11
        Pain/Discomfort @ Week 48|Some problems
    11
    14
        Anxiety/Depression @ Week 48|Some problems
    7
    6
        Mobility @ Week 60|Some problems
    0
    5
        Self-Care @ Week 60|Some problems
    0
    1
        Usual Activities @ Week 60|Some problems
    1
    7
        Pain/Discomfort @ Week 60|Some problems
    3
    8
        Anxiety/Depression @ Week 60|Some problems
    3
    9
        Mobility @ Week 72|Some problems
    1
    2
        Self-Care @ Week 72|Some problems
    0
    0
        Usual Activities @ Week 72|Some problems
    1
    7
        Pain/Discomfort @ Week 72|Some problems
    2
    6
        Anxiety/Depression @ Week 72|Some problems
    4
    6
        Mobility @ Week 84|Some problems
    1
    2
        Self-Care @ Week 84|Some problems
    0
    0
        Usual Activities @ Week 84|Some problems
    1
    2
        Pain/Discomfort @ Week 84|Some problems
    2
    6
        Anxiety/Depression @ Week 84|Some problems
    3
    4
        Mobility @ Week 96|Some problems
    0
    2
        Self-Care @ Week 96|Some problems
    0
    0
        Usual Activities @ Week 96|Some problems
    2
    2
        Pain/Discomfort @ Week 96|Some problems
    2
    4
        Anxiety/Depression @ Week 96|Some problems
    4
    2
        Mobility @ Week 120|Some problems
    0
    1
        Self-Care @ Week 120|Some problems
    0
    0
        Usual Activities @ Week 120|Some problems
    0
    1
        Pain/Discomfort @ Week 120|Some problems
    1
    1
        Anxiety/Depression @ Week 120|Some problems
    3
    0
        Mobility @ Week 144|Some problems
    0
    0
        Self-Care @ Week 144|Some problems
    0
    0
        Usual Activities @ Week 144|Some problems
    0
    0
        Pain/Discomfort @ Week 144|Some problems
    0
    0
        Anxiety/Depression @ Week 144|Some problems
    1
    0
        Mobility @ Week 12|Unable to perform the activity
    1
    0
        Self-Care @ Wk 12|Unable to perform the activity
    1
    1
        Usual Activities@Wk 12|Unable to perform activity
    5
    1
        Pain/Discomfort @ Wk 12|Unable to perform activity
    1
    0
        Anxiety/Depr. @ Wk 12|Unable to perform activity
    2
    0
        Mobility @ Week 24|Unable to perform the activity
    1
    0
        Self-Care @ Wk 24|Unable to perform the activity
    0
    0
        Usual Activities@Wk 24|Unable to perform activity
    1
    2
        Pain/Discomfort @ Wk 24|Unable to perform activity
    1
    1
        Anxiety/Depr. @ Wk 24|Unable to perform activity
    0
    1
        Mobility @ Week 36|Unable to perform the activity
    0
    0
        Self-Care @ Wk 36|Unable to perform the activity
    0
    0
        Usual Activities@Wk 36|Unable to perform activity
    0
    1
        Pain/Discomfort @ Wk 36|Unable to perform activity
    3
    1
        Anxiety/Depr. @ Wk 36|Unable to perform activity
    0
    0
        Mobility @ Week 48|Unable to perform the activity
    0
    0
        Self-Care @ Wk 48|Unable to perform the activity
    0
    0
        Usual Activities@Wk 48|Unable to perform activity
    0
    0
        Pain/Discomfort @ Wk 48|Unable to perform activity
    1
    0
        Anxiety/Depr. @ Wk 48|Unable to perform activity
    0
    1
        Mobility @ Week 60|Unable to perform the activity
    0
    0
        Self-Care @ Wk 60|Unable to perform the activity
    0
    0
        Usual Activities@Wk 60|Unable to perform activity
    0
    2
        Pain/Discomfort @ Wk 60|Unable to perform activity
    0
    2
        Anxiety/Depr. @ Wk 60|Unable to perform activity
    0
    0
        Mobility @ Week 72|Unable to perform the activity
    0
    0
        Self-Care @ Wk 72|Unable to perform the activity
    0
    0
        Usual Activities@Wk 72|Unable to perform activity
    0
    0
        Pain/Discomfort @ Wk 72|Unable to perform activity
    0
    0
        Anxiety/Depr. @ Wk 72|Unable to perform activity
    0
    1
        Mobility @ Week 84|Unable to perform the activity
    0
    0
        Self-Care @ Wk 84|Unable to perform the activity
    0
    0
        Usual Activities@Wk 84|Unable to perform activity
    0
    1
        Pain/Discomfort @ Wk 84|Unable to perform activity
    0
    0
        Anxiety/Depr.@Wk 84|Unable to perform activity
    0
    0
        Mobility @ Week 96|Unable to perform the activity
    0
    0
        Self-Care @ Wk 96|Unable to perform the activity
    0
    0
        Usual Activities@Wk 96|Unable to perform activity
    0
    0
        Pain/Discomfort @ Wk 96|Unable to perform activity
    1
    0
        Anxiety/Depr. @ Wk 96|Unable to perform activity
    0
    0
        Mobility @ Week 120|Unable to perform the activity
    0
    0
        Self-Care @ Wk 120|Unable to perform the activity
    0
    0
        Usual Activities@Wk 120|Unable to perform activity
    0
    0
        Pain/Discomfort@Wk 120|Unable to perform activity
    0
    0
        Anxiety/Depr. @ Wk 120|Unable to perform activity
    0
    0
        Mobility @ Week 144|Unable to perform the activity
    0
    0
        Self-Care @ Wk 144|Unable to perform the activity
    0
    0
        Usual Activities@Wk 144|Unable to perform activity
    0
    0
        Pain/Discomfort@Wk 144|Unable to perform activity
    0
    0
        Anxiety/Depr. @ Wk 144|Unable to perform activity
    0
    0
        Mobility @ Week 12|Missing
    0
    0
        Self-Care @ Week 12|Missing
    0
    1
        Usual Activities @ Week 12|Missing
    0
    0
        Pain/Discomfort @ Week 12|Missing
    1
    0
        Anxiety/Depression @ Week 12|Missing
    0
    0
        Mobility @ Week 24|Missing
    0
    0
        Self-Care @ Week 24|Missing
    0
    0
        Usual Activities @ Week 24|Missing
    0
    0
        Pain/Discomfort @ Week 24|Missing
    0
    0
        Anxiety/Depression @ Week 24|Missing
    0
    0
        Mobility @ Week 36|Missing
    0
    0
        Self-Care @ Week 36|Missing
    0
    0
        Usual Activities @ Week 36|Missing
    0
    0
        Pain/Discomfort @ Week 36|Missing
    0
    1
        Anxiety/Depression @ Week 36|Missing
    0
    0
        Mobility @ Week 48|Missing
    0
    0
        Self-Care @ Week 48|Missing
    0
    0
        Usual Activities @ Week 48|Missing
    0
    0
        Pain/Discomfort @ Week 48|Missing
    0
    1
        Anxiety/Depression @ Week 48|Missing
    1
    0
        Mobility @ Week 60|Missing
    0
    0
        Self-Care @ Week 60|Missing
    0
    0
        Usual Activities @ Week 60|Missing
    0
    0
        Pain/Discomfort @ Week 60|Missing
    0
    0
        Anxiety/Depression @ Week 60|Missing
    0
    0
        Mobility @ Week 72|Missing
    0
    0
        Self-Care @ Week 72|Missing
    0
    0
        Usual Activities @ Week 72|Missing
    0
    0
        Pain/Discomfort @ Week 72|Missing
    0
    0
        Anxiety/Depression @ Week 72|Missing
    0
    0
        Mobility @ Week 84|Missing
    0
    0
        Self-Care @ Week 84|Missing
    0
    0
        Usual Activities @ Week 84|Missing
    0
    0
        Pain/Discomfort @ Week 84|Missing
    0
    0
        Anxiety/Depression @ Week 84|Missing
    0
    0
        Mobility @ Week 96|Missing
    0
    0
        Self-Care @ Week 96|Missing
    0
    0
        Usual Activities @ Week 96|Missing
    0
    0
        Pain/Discomfort @ Week 96|Missing
    0
    0
        Anxiety/Depression @ Week 96|Missing
    0
    0
        Mobility @ Week 120|Missing
    0
    0
        Self-Care @ Week 120|Missing
    0
    0
        Usual Activities @ Week 120|Missing
    0
    0
        Pain/Discomfort @ Week 120|Missing
    0
    0
        Anxiety/Depression @ Week 120|Missing
    0
    0
        Mobility @ Week 144|Missing
    0
    0
        Self-Care @ Week 144|Missing
    0
    0
        Usual Activities @ Week 144|Missing
    0
    0
        Pain/Discomfort @ Week 144|Missing
    0
    0
        Anxiety/Depression @ Week 144|Missing
    0
    0
        Mobility @ Week 12|Not Done
    0
    0
        Self-Care @ Week 12|Not Done
    0
    0
        Usual Activities @ Week 12|Not Done
    0
    0
        Pain/Discomfort @ Week 12|Not Done
    0
    0
        Anxiety/Depression @ Week 12|Not Done
    0
    0
        Mobility @ Week 24|Not Done
    0
    0
        Self-Care @ Week 24|Not Done
    0
    0
        Usual Activities @ Week 24|Not Done
    0
    0
        Pain/Discomfort @ Week 24|Not Done
    0
    0
        Anxiety/Depression @ Week 24|Not Done
    0
    0
        Mobility @ Week 36|Not Done
    0
    0
        Self-Care @ Week 36|Not Done
    1
    0
        Usual Activities @ Week 36|Not Done
    1
    0
        Pain/Discomfort @ Week 36|Not Done
    1
    0
        Anxiety/Depression @ Week 36|Not Done
    1
    0
        Mobility @ Week 48|Not Done
    0
    0
        Self-Care @ Week 48|Not Done
    0
    0
        Usual Activities @ Week 48|Not Done
    0
    0
        Pain/Discomfort @ Week 48|Not Done
    0
    0
        Anxiety/Depression @ Week 48|Not Done
    0
    0
        Mobility @ Week 60|Not Done
    0
    0
        Self-Care @ Week 60|Not Done
    0
    0
        Usual Activities @ Week 60|Not Done
    0
    0
        Pain/Discomfort @ Week 60|Not Done
    0
    0
        Anxiety/Depression @ Week 60|Not Done
    0
    0
        Mobility @ Week 72|Not Done
    0
    0
        Self-Care @ Week 72|Not Done
    0
    0
        Usual Activities @ Week 72|Not Done
    0
    0
        Pain/Discomfort @ Week 72|Not Done
    0
    0
        Anxiety/Depression @ Week 72|Not Done
    0
    0
        Mobility @ Week 84|Not Done
    0
    0
        Self-Care @ Week 84|Not Done
    0
    0
        Usual Activities @ Week 84|Not Done
    0
    0
        Pain/Discomfort @ Week 84|Not Done
    0
    0
        Anxiety/Depression @ Week 84|Not Done
    0
    0
        Mobility @ Week 96|Not Done
    0
    0
        Self-Care @ Week 96|Not Done
    0
    0
        Usual Activities @ Week 96|Not Done
    0
    0
        Pain/Discomfort @ Week 96|Not Done
    0
    0
        Anxiety/Depression @ Week 96|Not Done
    0
    0
        Mobility @ Week 120|Not Done
    0
    0
        Self-Care @ Week 120|Not Done
    0
    0
        Usual Activities @ Week 120|Not Done
    0
    0
        Pain/Discomfort @ Week 120|Not Done
    0
    0
        Anxiety/Depression @ Week 120|Not Done
    0
    0
        Mobility @ Week 144|Not Done
    0
    0
        Self-Care @ Week 144|Not Done
    0
    0
        Usual Activities @ Week 144|Not Done
    0
    0
        Pain/Discomfort @ Week 144|Not Done
    0
    0
        Anxiety/Depression @ Week 144|Not Done
    0
    0
    No statistical analyses for this end point

    Secondary: Change in EORTC QLQ-C30 Global Score from Baseline to 12 Weeks

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    End point title
    		 Change in EORTC QLQ-C30 Global Score from Baseline to 12 Weeks
    End point description
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30) is a questionnaire developed to assess the quality of life of cancer patients. The global score ranges from 0-100, with higher values representing a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    260
    266
    Units: Score on global scale
        arithmetic mean (standard deviation)
    61.67 ± 20.93
    64.41 ± 20.18
    No statistical analyses for this end point

    Secondary: Change from Baseline in the EQ-VAS score (Canadian and Australian centers only)

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    End point title
    		 Change from Baseline in the EQ-VAS score (Canadian and Australian centers only)
    End point description
    The European Quality of Life (EuroQol) – 5 Domain (EQ-5D) self-administered questionnaire consists of two pages comprising the EQ-5D descriptive system and the EQ Visual Analogue Scale (VAS). The EQ VAS records the patient’s self-rated health on a vertical visual analogue 0-100 scale, where the endpoints are labelled ‘The best health you can imagine’ (100) and ‘The worst health you can imagine’ (0).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week 120, Week 144
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    55
    43
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 12
    1.6 ± 17.16
    7.0 ± 19.30
        Week 24
    -1.5 ± 21.98
    1.3 ± 21.56
        Week 36
    0.4 ± 21.86
    5.9 ± 22.53
        Week 48
    5.2 ± 23.17
    6.5 ± 25.37
        Week 60
    5.8 ± 10.51
    7.9 ± 28.29
        Week 72
    10.1 ± 7.36
    11.8 ± 29.96
        Week 84
    5.2 ± 6.46
    4.9 ± 25.08
        Week 96
    3.0 ± 19.90
    -10.0 ± 10.80
        Week 120
    10.3 ± 5.91
    -11.0 ± 13.11
        Week 144
    13.0 ± 999
    4.0 ± 999
    No statistical analyses for this end point

    Secondary: Number of participant hospitalized (Canadian and Australian centers only)

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    End point title
    		 Number of participant hospitalized (Canadian and Australian centers only)
    End point description
    The number of hospitalizations were categorized: >0 and =<2, >2 and =<4 and >4.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 28 days safety follow-up, assessed up to 40 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Participants
        > 0 and =< 2
    27
    16
        > 2 and =< 4
    1
    0
        > 4
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Healthcare Utilization (Canadian and Australian centers only)

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    End point title
    		 Number of Participants with Healthcare Utilization (Canadian and Australian centers only)
    End point description
    The measures of healthcare resource utilization collected were categorized: hospitalization/inpatient visit, Institutionalized, Outpatient visit.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 28 days safety follow-up, assessed up to 40 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Participants
        Hospitalization/Inpatient visit
    29
    17
        Institutionalized
    0
    2
        Outpatient Visit
    52
    45
    No statistical analyses for this end point

    Secondary: Reasons for hospitalization (Canadian and Australian centers only)

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    End point title
    		 Reasons for hospitalization (Canadian and Australian centers only)
    End point description
    The reasons for hospitalization were categorized: Breast Cancer, Febrile Neutropenia, Infection, Other and Pneumonia.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 28 days safety follow-up, assessed up to 40 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Participants
        Breast Cancer
    3
    3
        Febrile neutropenia
    10
    1
        Infection
    5
    4
        Other
    14
    9
        Pneumonia
    2
    1
    No statistical analyses for this end point

    Secondary: Total and average duration of hospitalization (Canadian and Australian centers only)

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    End point title
    		 Total and average duration of hospitalization (Canadian and Australian centers only)
    End point description
    The total duration of hospitalization in days and average duration of each hospitalization in days were summarized using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 28 days safety follow-up, assessed up to 40 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Days
    arithmetic mean (standard deviation)
        Total duration of hospitalization
    10.38 ± 10.63
    16.18 ± 38.63
        Average duration of each hospitalization
    6.6 ± 5.46
    6.5 ± 4.81
    No statistical analyses for this end point

    Secondary: Type of ward (hospital unit) (Canadian and Australian centers only)

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    End point title
    		 Type of ward (hospital unit) (Canadian and Australian centers only)
    End point description
    The type of ward (hospital unit) were categorized: general ward, intensive care unit, oncology ward, rehabilitation unit and other.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 28 days safety follow-up, assessed up to 40 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Participants
        General ward
    12
    9
        Intensive care unit
    1
    1
        Oncology ward
    13
    9
        Other
    6
    3
        Rehabilitation unit
    0
    1
    No statistical analyses for this end point

    Secondary: Discharge Destinations (Canadian and Australian centers only)

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    End point title
    		 Discharge Destinations (Canadian and Australian centers only)
    End point description
    The discharge destinations were categorized: died, home, rehabilitation facility and transfer to other hospital.
    End point type
    Secondary
    End point timeframe
    From date of randomization till 28 days safety follow-up, assessed up to 40 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    56
    49
    Units: Participants
        Died
    1
    1
        Home
    26
    14
        Rehabilitation facility
    0
    1
        Transfer to other hospital
    1
    1
    No statistical analyses for this end point

    Secondary: Estrogen receptor (ER) and Progesterone receptor (PgR) status

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    End point title
    		 Estrogen receptor (ER) and Progesterone receptor (PgR) status
    End point description
    Immunohistochemistry (IHC) analysis of estrogen receptor (ER) and progesterone receptor (PgR) were performed as part of the mandatory central laboratory testing for protocol-specified biomarkers.
    End point type
    Secondary
    End point timeframe
    Up to approximately 39 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T)
    Number of subjects analysed
    326
    326
    Units: Percentage of Participants
        estrogen receptor (ER) positive
    65
    64
        progesterone receptor (PgR) negative
    58
    63
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    On-treatment deaths were collected from first dose of study medication to 28 days after the last dose of study medication, for a maximum duration of approximately 165 months. Post-treatment survival follow-up deaths were collected from day 29 after last dose of study medication to end of study, up to approximately 166 months. All deaths refer to the sum of on-treatment deaths and post-treatment survival follow-up deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment deaths: Up to approximately 165 months. Post-treatment survival follow-up deaths: Up to approximately 166 months
    End point values
    		 Lapatinib (LTax/L) Trastuzumab (TTax/T) Crossed over to Trastuzumab (TTax/T) after IA results
    Number of subjects analysed
    322
    325
    5
    Units: Participants
        On-treatment deaths
    21
    13
    0
        Post-treatment survival follow-up deaths
    82
    73
    0
        All deaths
    103
    86
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 28 days, up to a maximum duration of approximately 165 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    LTax/L [1]
    Reporting group description
    		 LTax/L [1]

    Reporting group title
    Crossed over to TTax/T after IA results [2]
    Reporting group description
    		 Crossed over to TTax/T after IA results [2]

    Reporting group title
    TTax/T
    Reporting group description
    		 TTax/T

    Serious adverse events
    		 LTax/L [1] Crossed over to TTax/T after IA results [2] TTax/T
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 322 (32.92%)
    2 / 5 (40.00%)
    66 / 325 (20.31%)
         number of deaths (all causes)
    21
    0
    13
         number of deaths resulting from adverse events
    2
    0
    1
    Vascular disorders
    Syncope
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Hypertension
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Haematoma
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Embolism
         subjects affected / exposed
    5 / 322 (1.55%)
    0 / 5 (0.00%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cerebral ischaemia
         subjects affected / exposed
    2 / 322 (0.62%)
    1 / 5 (20.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Uterine haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Ulcer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Pyrexia
         subjects affected / exposed
    7 / 322 (2.17%)
    0 / 5 (0.00%)
    9 / 325 (2.77%)
         occurrences causally related to treatment / all
    5 / 8
    0 / 0
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    16 / 322 (4.97%)
    0 / 5 (0.00%)
    8 / 325 (2.46%)
         occurrences causally related to treatment / all
    18 / 18
    0 / 0
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    5 / 322 (1.55%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Sexual dysfunction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    5 / 322 (1.55%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    0 / 325 (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
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    14 / 322 (4.35%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    10 / 15
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase
         subjects affected / exposed
    7 / 322 (2.17%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin
         subjects affected / exposed
    7 / 322 (2.17%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    0 / 325 (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
    Neutrophil count
         subjects affected / exposed
    6 / 322 (1.86%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Injection site reaction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Seroma
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Sudden death
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Muscular weakness
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multifocal motor neuropathy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Headache
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Confusional state
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Blood and lymphatic system disorders
    Platelet disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    23 / 322 (7.14%)
    0 / 5 (0.00%)
    5 / 325 (1.54%)
         occurrences causally related to treatment / all
    37 / 39
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Abdominal pain
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    0 / 325 (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
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Vomiting
         subjects affected / exposed
    12 / 322 (3.73%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    15 / 19
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    0 / 325 (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
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Pancreatitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    6 / 322 (1.86%)
    0 / 5 (0.00%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    7 / 9
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Ileus
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    0 / 325 (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
    Hepatobiliary disorders
    Hepatobiliary disease
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Skin and subcutaneous tissue disorders
    Skin infection
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    4 / 322 (1.24%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Kidney infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Pain in extremity
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Myalgia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 5 (20.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 5 (0.00%)
    0 / 325 (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
    Infections and infestations
    Paronychia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Infection
         subjects affected / exposed
    10 / 322 (3.11%)
    0 / 5 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    4 / 11
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    5 / 322 (1.55%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 322 (2.17%)
    0 / 5 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    3 / 11
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (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
    Upper aerodigestive tract infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 322 (1.24%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 322 (1.24%)
    0 / 5 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 5 (0.00%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LTax/L [1] Crossed over to TTax/T after IA results [2] TTax/T
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    316 / 322 (98.14%)
    1 / 5 (20.00%)
    319 / 325 (98.15%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    16 / 322 (4.97%)
    0 / 5 (0.00%)
    22 / 325 (6.77%)
         occurrences all number
    17
    0
    23
    Vascular disorders
    Hot flush
         subjects affected / exposed
    27 / 322 (8.39%)
    0 / 5 (0.00%)
    32 / 325 (9.85%)
         occurrences all number
    28
    0
    35
    Lymphoedema
         subjects affected / exposed
    17 / 322 (5.28%)
    0 / 5 (0.00%)
    12 / 325 (3.69%)
         occurrences all number
    23
    0
    13
    Epistaxis
         subjects affected / exposed
    63 / 322 (19.57%)
    0 / 5 (0.00%)
    43 / 325 (13.23%)
         occurrences all number
    91
    0
    59
    Hypertension
         subjects affected / exposed
    22 / 322 (6.83%)
    0 / 5 (0.00%)
    37 / 325 (11.38%)
         occurrences all number
    25
    0
    39
    Flushing
         subjects affected / exposed
    19 / 322 (5.90%)
    0 / 5 (0.00%)
    14 / 325 (4.31%)
         occurrences all number
    34
    0
    24
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    51 / 322 (15.84%)
    0 / 5 (0.00%)
    54 / 325 (16.62%)
         occurrences all number
    68
    0
    65
    Fatigue
         subjects affected / exposed
    225 / 322 (69.88%)
    0 / 5 (0.00%)
    212 / 325 (65.23%)
         occurrences all number
    345
    0
    390
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    30 / 322 (9.32%)
    1 / 5 (20.00%)
    45 / 325 (13.85%)
         occurrences all number
    37
    1
    63
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    24 / 322 (7.45%)
    0 / 5 (0.00%)
    29 / 325 (8.92%)
         occurrences all number
    26
    0
    32
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    75 / 322 (23.29%)
    0 / 5 (0.00%)
    85 / 325 (26.15%)
         occurrences all number
    102
    0
    107
    Cough
         subjects affected / exposed
    69 / 322 (21.43%)
    0 / 5 (0.00%)
    94 / 325 (28.92%)
         occurrences all number
    80
    0
    113
    Rhinitis allergic
         subjects affected / exposed
    30 / 322 (9.32%)
    0 / 5 (0.00%)
    21 / 325 (6.46%)
         occurrences all number
    32
    0
    26
    Oropharyngeal pain
         subjects affected / exposed
    15 / 322 (4.66%)
    0 / 5 (0.00%)
    30 / 325 (9.23%)
         occurrences all number
    18
    0
    33
    Influenza
         subjects affected / exposed
    23 / 322 (7.14%)
    0 / 5 (0.00%)
    30 / 325 (9.23%)
         occurrences all number
    35
    0
    51
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    65 / 322 (20.19%)
    0 / 5 (0.00%)
    72 / 325 (22.15%)
         occurrences all number
    75
    0
    99
    Dysphonia
         subjects affected / exposed
    8 / 322 (2.48%)
    0 / 5 (0.00%)
    21 / 325 (6.46%)
         occurrences all number
    8
    0
    34
    Depressed mood
         subjects affected / exposed
    27 / 322 (8.39%)
    0 / 5 (0.00%)
    30 / 325 (9.23%)
         occurrences all number
    31
    0
    33
    Anxiety
         subjects affected / exposed
    34 / 322 (10.56%)
    0 / 5 (0.00%)
    34 / 325 (10.46%)
         occurrences all number
    36
    0
    38
    Investigations
    Weight increased
         subjects affected / exposed
    6 / 322 (1.86%)
    0 / 5 (0.00%)
    17 / 325 (5.23%)
         occurrences all number
    6
    0
    19
    Weight decreased
         subjects affected / exposed
    29 / 322 (9.01%)
    0 / 5 (0.00%)
    14 / 325 (4.31%)
         occurrences all number
    30
    0
    15
    Gamma-glutamyltransferase
         subjects affected / exposed
    20 / 322 (6.21%)
    0 / 5 (0.00%)
    10 / 325 (3.08%)
         occurrences all number
    24
    0
    12
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    9 / 322 (2.80%)
    0 / 5 (0.00%)
    21 / 325 (6.46%)
         occurrences all number
    12
    0
    23
    Oedema peripheral
         subjects affected / exposed
    86 / 322 (26.71%)
    0 / 5 (0.00%)
    113 / 325 (34.77%)
         occurrences all number
    107
    0
    147
    Left ventricular dysfunction
         subjects affected / exposed
    9 / 322 (2.80%)
    0 / 5 (0.00%)
    25 / 325 (7.69%)
         occurrences all number
    11
    0
    26
    Nervous system disorders
    Vision blurred
         subjects affected / exposed
    16 / 322 (4.97%)
    0 / 5 (0.00%)
    17 / 325 (5.23%)
         occurrences all number
    17
    0
    17
    Peripheral sensory neuropathy
         subjects affected / exposed
    168 / 322 (52.17%)
    0 / 5 (0.00%)
    165 / 325 (50.77%)
         occurrences all number
    204
    0
    197
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    30 / 322 (9.32%)
    0 / 5 (0.00%)
    10 / 325 (3.08%)
         occurrences all number
    34
    0
    11
    Multifocal motor neuropathy
         subjects affected / exposed
    16 / 322 (4.97%)
    0 / 5 (0.00%)
    21 / 325 (6.46%)
         occurrences all number
    18
    0
    22
    Headache
         subjects affected / exposed
    66 / 322 (20.50%)
    0 / 5 (0.00%)
    72 / 325 (22.15%)
         occurrences all number
    106
    0
    112
    Dizziness
         subjects affected / exposed
    36 / 322 (11.18%)
    0 / 5 (0.00%)
    51 / 325 (15.69%)
         occurrences all number
    41
    0
    61
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    26 / 322 (8.07%)
    0 / 5 (0.00%)
    37 / 325 (11.38%)
         occurrences all number
    31
    0
    42
    Gastrointestinal disorders
    Taste disorder
         subjects affected / exposed
    55 / 322 (17.08%)
    0 / 5 (0.00%)
    51 / 325 (15.69%)
         occurrences all number
    74
    0
    68
    Stomatitis
         subjects affected / exposed
    138 / 322 (42.86%)
    0 / 5 (0.00%)
    106 / 325 (32.62%)
         occurrences all number
    233
    0
    215
    Nausea
         subjects affected / exposed
    157 / 322 (48.76%)
    0 / 5 (0.00%)
    139 / 325 (42.77%)
         occurrences all number
    290
    0
    232
    Dyspepsia
         subjects affected / exposed
    67 / 322 (20.81%)
    0 / 5 (0.00%)
    61 / 325 (18.77%)
         occurrences all number
    90
    0
    87
    Dry mouth
         subjects affected / exposed
    19 / 322 (5.90%)
    0 / 5 (0.00%)
    12 / 325 (3.69%)
         occurrences all number
    27
    0
    15
    Diarrhoea
         subjects affected / exposed
    250 / 322 (77.64%)
    0 / 5 (0.00%)
    130 / 325 (40.00%)
         occurrences all number
    689
    0
    275
    Constipation
         subjects affected / exposed
    74 / 322 (22.98%)
    0 / 5 (0.00%)
    85 / 325 (26.15%)
         occurrences all number
    101
    0
    115
    Abdominal pain upper
         subjects affected / exposed
    21 / 322 (6.52%)
    0 / 5 (0.00%)
    14 / 325 (4.31%)
         occurrences all number
    25
    0
    17
    Abdominal pain
         subjects affected / exposed
    51 / 322 (15.84%)
    0 / 5 (0.00%)
    40 / 325 (12.31%)
         occurrences all number
    62
    0
    54
    Abdominal distension
         subjects affected / exposed
    18 / 322 (5.59%)
    0 / 5 (0.00%)
    8 / 325 (2.46%)
         occurrences all number
    21
    0
    8
    Vomiting
         subjects affected / exposed
    92 / 322 (28.57%)
    0 / 5 (0.00%)
    75 / 325 (23.08%)
         occurrences all number
    161
    0
    109
    Skin and subcutaneous tissue disorders
    Skin infection
         subjects affected / exposed
    12 / 322 (3.73%)
    0 / 5 (0.00%)
    19 / 325 (5.85%)
         occurrences all number
    17
    0
    20
    Skin disorder
         subjects affected / exposed
    25 / 322 (7.76%)
    0 / 5 (0.00%)
    20 / 325 (6.15%)
         occurrences all number
    36
    0
    31
    Rash
         subjects affected / exposed
    192 / 322 (59.63%)
    0 / 5 (0.00%)
    127 / 325 (39.08%)
         occurrences all number
    321
    0
    194
    Pruritus
         subjects affected / exposed
    47 / 322 (14.60%)
    0 / 5 (0.00%)
    38 / 325 (11.69%)
         occurrences all number
    61
    0
    60
    Nail disorder
         subjects affected / exposed
    129 / 322 (40.06%)
    0 / 5 (0.00%)
    88 / 325 (27.08%)
         occurrences all number
    135
    0
    96
    Dry skin
         subjects affected / exposed
    59 / 322 (18.32%)
    0 / 5 (0.00%)
    40 / 325 (12.31%)
         occurrences all number
    67
    0
    45
    Alopecia
         subjects affected / exposed
    212 / 322 (65.84%)
    0 / 5 (0.00%)
    238 / 325 (73.23%)
         occurrences all number
    216
    0
    245
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    75 / 322 (23.29%)
    0 / 5 (0.00%)
    99 / 325 (30.46%)
         occurrences all number
    112
    0
    154
    Chills
         subjects affected / exposed
    7 / 322 (2.17%)
    0 / 5 (0.00%)
    22 / 325 (6.77%)
         occurrences all number
    7
    0
    22
    Bone pain
         subjects affected / exposed
    69 / 322 (21.43%)
    0 / 5 (0.00%)
    79 / 325 (24.31%)
         occurrences all number
    86
    0
    110
    Back pain
         subjects affected / exposed
    55 / 322 (17.08%)
    0 / 5 (0.00%)
    72 / 325 (22.15%)
         occurrences all number
    61
    0
    90
    Myalgia
         subjects affected / exposed
    79 / 322 (24.53%)
    1 / 5 (20.00%)
    78 / 325 (24.00%)
         occurrences all number
    114
    1
    140
    Pain in extremity
         subjects affected / exposed
    37 / 322 (11.49%)
    0 / 5 (0.00%)
    52 / 325 (16.00%)
         occurrences all number
    48
    0
    61
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    38 / 322 (11.80%)
    0 / 5 (0.00%)
    43 / 325 (13.23%)
         occurrences all number
    43
    0
    66
    Paronychia
         subjects affected / exposed
    29 / 322 (9.01%)
    0 / 5 (0.00%)
    11 / 325 (3.38%)
         occurrences all number
    39
    0
    12
    Cystitis
         subjects affected / exposed
    15 / 322 (4.66%)
    0 / 5 (0.00%)
    22 / 325 (6.77%)
         occurrences all number
    16
    0
    27
    Rhinitis
         subjects affected / exposed
    27 / 322 (8.39%)
    0 / 5 (0.00%)
    31 / 325 (9.54%)
         occurrences all number
    30
    0
    40
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    107 / 322 (33.23%)
    0 / 5 (0.00%)
    74 / 325 (22.77%)
         occurrences all number
    157
    0
    97

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2008
    Amendment 1: Updated background information for emerging data regarding hepatotoxicity seen with the use of lapatinib. To reflect changes due to updated lapatinib investigator’s brochure. To clarify protocol regarding the study logistics, requirements for supporting documents, lapatinib tablet information and eligibility assessments.
    07 Jan 2010
    Amendment 2: To reflect changes in study logistics with regard to central disease assessment review and to add protocol clarifications throughout regarding assessments, CRFs and prohibited medications.
    16 Feb 2010
    Amendment 3: Safety amendment to require use of primary prophylactic treatment with G-CSF during combination therapy phase for subjects randomized to the lapatinib + docetaxel arm. Diarrhea management guidelines were also updated to reflect most current information for lapatinib.
    22 Apr 2010
    Amendment 4: To clarify eligibility criteria on cardiac illness and acceptance of slides of tumor tissue when blocks unavailable. Updated to describe the additional OS analysis that was conducted following completion of the final analysis for PFS. Updated to add protocol clarifications throughout regarding assessments, supporting documents and use of cimetidine per institutional practice.
    15 Jun 2012
    Amendment 5: To reflect changes in protocol conduct following disclosure of the results of the planned interim analysis of the study. Main changes included reduction of assessments and data collection and clarification on CRFs for submission.
    08 Apr 2014
    Amendment 6: To reflect changes in study conduct with removal of NCIC CTG from all aspects of ongoing study conduct. Further reduction in assessments as study is a long-term follow-up study. Updated to add prohibited medications list, updated diarrhea management guidelines.
    23 Mar 2016
    Amendment 7: Deleted or replaced references to GSK or its staff with that of Novartis and its authorized agents to align with the change of sponsorship. Made administrative changes to align with Novartis processes and procedures.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25779558
    http://www.ncbi.nlm.nih.gov/pubmed/28484925
    http://www.ncbi.nlm.nih.gov/pubmed/28750133
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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