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    Clinical Trial Results:
    A randomized, multicenter open-label phase III study of neoadjuvant lapatinib, trastuzumab and their combination plus paclitaxel in women with HER2/ErbB2 positive primary breast cancer

    Summary
    EudraCT number
    		 2006-000564-81
    Trial protocol
    		 FR   DE   BE   GB   LT   GR   HU   ES   IT   SE  
    Global end of trial date
    23 Dec 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    09 Sep 2021
    First version publication date
    06 Jan 2021
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    EGF106903
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00553358
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CLAP016B2302: CLAP016B2302
    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
    23 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in subjects with HER2 overexpressing or amplified operable breast cancer randomized to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib, trastuzumab plus paclitaxel.
    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
    05 Jan 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: 17
    Country: Number of subjects enrolled
    Belgium: 33
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Peru: 39
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    South Africa: 26
    Country: Number of subjects enrolled
    Spain: 45
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Taiwan: 57
    Country: Number of subjects enrolled
    Ukraine: 23
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    455
    EEA total number of subjects
    201
    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)
    403
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was a parallel group, three-arm, randomized, multicenter, open-label phase III study. The study compared the efficacy and tolerability of neoadjuvant lapatinib and paclitaxel, versus trastuzumab and paclitaxel, versus the combination of lapatinib with trastuzumab and paclitaxel.

    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 1000/750 mg + Trastuzumab 2 mg/kg
    Arm description
    		 Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    LAP016
    Other name
    GW572016
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral lapatinib (1000 mg daily) plus trastuzumab (4 mg/kg iv load followed by 2 mg/kg iv weekly) for 6 weeks, followed by lapatinib (750 mg daily) plus trastuzumab (2 mg/kg iv weekly) plus weekly paclitaxel (80 mg/m2 iv) for an additional 12 weeks.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solvent for parenteral use
    Routes of administration
    Parenteral use
    Dosage and administration details
    Oral lapatinib (1000 mg daily) plus trastuzumab (4 mg/kg iv load followed by 2 mg/kg iv weekly) for 6 weeks, followed by lapatinib (750 mg daily) plus trastuzumab (2 mg/kg iv weekly) plus weekly paclitaxel (80 mg/m2 iv) for an additional 12 weeks.

    Arm title
    		 Lapatinib 1500 mg
    Arm description
    		 Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    LAP016
    Other name
    GW572016
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral lapatinib (1500 mg daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg/m2 iv) for an additional 12 weeks

    Arm title
    		 Trastuzumab 2 mg/kg
    Arm description
    		 Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solvent for parenteral use
    Routes of administration
    Parenteral use
    Dosage and administration details
    Trastuzumab (4 mg/kg iv load followed by 2 mg/kg iv weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m2 iv) for an additional 12 weeks

    Number of subjects in period 1
    		Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Started
    152
    154
    149
    Completed
    73
    58
    61
    Not completed
    79
    96
    88
         Died during clinical follow-up
    25
    29
    32
         Randomized but did not receive treatment
    3
    3
    1
         Died after clinical follow-up ended
    1
    2
    -
         W/drew (survival only)–alive at end of f/up
    1
    1
    1
         Not dead but were last f/up prior to year 10
    4
    2
    2
         Lost to follow-up
    22
    26
    18
         Withdrew completely
    23
    33
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
    Reporting group description
    		 Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks

    Reporting group title
    Lapatinib 1500 mg
    Reporting group description
    		 Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks

    Reporting group title
    Trastuzumab 2 mg/kg
    Reporting group description
    		 Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks

    Reporting group values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg Total
    Number of subjects
    		 152 154 149 455
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 130 137 136 403
        From 65-84 years
    		 22 17 13 52
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 152 154 149 455
        Male
    		 0 0 0 0
    GenderNIH
    Units: Subjects
        Female
    		 152 154 149 455
        Male
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 15 13 14 42
        Asian - Central/South
    		 5 7 5 17
        Asian - East
    		 31 30 28 89
        Asian - South East
    		 2 0 0 2
        Black or African American/African Heritage
    		 4 0 4 8
        White - Arabic/North African Heritage
    		 3 6 5 14
        White - Caucasian European Heritage
    		 92 97 93 282
        Missing
    		 0 1 0 1
    Number of participants with tumor cells of the indicated histologic grade
    Histologic grade, also called differentiation, refers to how much the tumor cells resemble normal cells of the same tissue type.
    Units: Subjects
        Well differentiated
    		 5 2 5 12
        Moderately differentiated
    		 63 56 53 172
        Poorly differentiated
    		 64 73 68 205
        Differentiation cannot be assessed
    		 20 22 23 65
        Missing
    		 0 1 0 1
    Number of participants with lymph nodes (LNs) of the indicated clinical N stage
    Clinical N stage is an evaluation/staging of LN status through physical examination. N0, no regional LN metastasis; N1, metastasis to movable ipsilateral axillary LNs (IALNs); N2a, metastasis in IALNs fixed to one another (matted) or the other structures; N2b, metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary LN metastasis; N3a, metastasis in ipsilateral infraclavicular LNs; N3b, metastasis in ipsilateral internal mammary LNs fixed and axillary LN; N3c, metastasis in ipsilateral subclavicar LNs; Nx, not assessed.
    Units: Subjects
        N 0
    		 48 34 41 123
        N 1
    		 80 95 85 260
        N2 (including N2a and N2b)
    		 15 19 13 47
        N3 (including N3a, N3b, and N3c)
    		 6 6 7 19
        N x
    		 3 0 3 6
    Number of participants with the indicated IHC results
    An Immunohistochemistry (IHC) test gives a score of 0 to 3+, which indicates the amount of Human Epidermal Growth Factor (HER2) receptor proteins on the cancer cells in the sample tissue. A positive score (3+) indicates that HER2 receptor protein is present, a negative score (0-1+) indicates that no HER2 receptor protein is present, and an equivocal score (2+) indicates uncertainty and a result that is open for interpretation. Equivocal results require additional testing. “Not applicable” refers to the number of participants who did not have IHC testing done.
    Units: Subjects
        Not applicable
    		 61 60 53 174
        Equivocal: Score of 2+
    		 8 9 5 22
        Positive: Score of 3+
    		 76 81 89 246
        Negative: Score of 0-1+
    		 3 0 1 4
        Non interpretable
    		 4 4 1 9
    Number of participants with the indicated FISH results
    The Fluorescent In Situ Hybridization (FISH) assay was used to determine the overexpression and/or amplification of HER2 in the invasive component of the primary tumor. Amplified indicates that the cell is overexpressing copies of the HER2 gene. Not amplified indicates that there is no overexpression of copies of the HER2 gene. “Not applicable” refers to the number of participants who did not have the FISH assay performed.
    Units: Subjects
        Not applicable
    		 41 38 42 121
        Amplified
    		 109 115 105 329
        Not amplified
    		 1 1 2 4
        Not interpretable
    		 1 0 0 1
    AgeContinuous
    Units: Years
        median (full range (min-max))
    		 50.0 (25 to 80) 50.0 (28 to 79) 49.0 (23 to 77) -
    Subject analysis sets

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Overall - of the 3 arms

    Subject analysis set title
    pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    locoregional pathological Complete Response (pCR)

    Subject analysis set title
    No pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    no locoregional pathological Complete Response (pCR)

    Subject analysis set title
    pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    locoregional pathological Complete Response (pCR)

    Subject analysis set title
    No pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    no locoregional pathological Complete Response (pCR)

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Overall - of the 3 arms

    Subject analysis sets values
    		 Overall pathological Complete Response (pCR) No pathological Complete Response (pCR) pathological Complete Response (pCR) No pathological Complete Response (pCR) Overall
    Number of subjects
    410
    136
    274
    137
    283
    420
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    403
        From 65-84 years
    52
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    455
        Male
    0
    GenderNIH
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
        Asian - Central/South
        Asian - East
        Asian - South East
        Black or African American/African Heritage
        White - Arabic/North African Heritage
        White - Caucasian European Heritage
        Missing
    Number of participants with tumor cells of the indicated histologic grade
    Histologic grade, also called differentiation, refers to how much the tumor cells resemble normal cells of the same tissue type.
    Units: Subjects
        Well differentiated
        Moderately differentiated
        Poorly differentiated
        Differentiation cannot be assessed
        Missing
    Number of participants with lymph nodes (LNs) of the indicated clinical N stage
    Clinical N stage is an evaluation/staging of LN status through physical examination. N0, no regional LN metastasis; N1, metastasis to movable ipsilateral axillary LNs (IALNs); N2a, metastasis in IALNs fixed to one another (matted) or the other structures; N2b, metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary LN metastasis; N3a, metastasis in ipsilateral infraclavicular LNs; N3b, metastasis in ipsilateral internal mammary LNs fixed and axillary LN; N3c, metastasis in ipsilateral subclavicar LNs; Nx, not assessed.
    Units: Subjects
        N 0
        N 1
        N2 (including N2a and N2b)
        N3 (including N3a, N3b, and N3c)
        N x
    Number of participants with the indicated IHC results
    An Immunohistochemistry (IHC) test gives a score of 0 to 3+, which indicates the amount of Human Epidermal Growth Factor (HER2) receptor proteins on the cancer cells in the sample tissue. A positive score (3+) indicates that HER2 receptor protein is present, a negative score (0-1+) indicates that no HER2 receptor protein is present, and an equivocal score (2+) indicates uncertainty and a result that is open for interpretation. Equivocal results require additional testing. “Not applicable” refers to the number of participants who did not have IHC testing done.
    Units: Subjects
        Not applicable
        Equivocal: Score of 2+
        Positive: Score of 3+
        Negative: Score of 0-1+
        Non interpretable
    Number of participants with the indicated FISH results
    The Fluorescent In Situ Hybridization (FISH) assay was used to determine the overexpression and/or amplification of HER2 in the invasive component of the primary tumor. Amplified indicates that the cell is overexpressing copies of the HER2 gene. Not amplified indicates that there is no overexpression of copies of the HER2 gene. “Not applicable” refers to the number of participants who did not have the FISH assay performed.
    Units: Subjects
        Not applicable
        Amplified
        Not amplified
        Not interpretable
    AgeContinuous
    Units: Years
        median (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
    Reporting group description
    		 Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks

    Reporting group title
    Lapatinib 1500 mg
    Reporting group description
    		 Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks

    Reporting group title
    Trastuzumab 2 mg/kg
    Reporting group description
    		 Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Overall - of the 3 arms

    Subject analysis set title
    pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    locoregional pathological Complete Response (pCR)

    Subject analysis set title
    No pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    no locoregional pathological Complete Response (pCR)

    Subject analysis set title
    pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    locoregional pathological Complete Response (pCR)

    Subject analysis set title
    No pathological Complete Response (pCR)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    no locoregional pathological Complete Response (pCR)

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Overall - of the 3 arms

    Primary: Number of participants with pathological complete response (pCR) at the time of surgery

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    End point title
    		 Number of participants with pathological complete response (pCR) at the time of surgery
    End point description
    Pathological complete response is defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, which do not take into account the histological nodal status.
    End point type
    Primary
    End point timeframe
    Weeks 20 to 22
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: participants
    78
    38
    44
    Statistical analysis title
    		 Participants with pCR at the time of surgery
    Comparison groups
    Lapatinib 1500 mg v Trastuzumab 2 mg/kg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3416
    Method
    		 Binomial
    Parameter type
    		 Percentage of participants with pCR
    Point estimate
    -4.85
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -17.6
         upper limit
    		 8.16
    Statistical analysis title
    		 Participants with pCR at the time of surgery
    Comparison groups
    Trastuzumab 2 mg/kg v Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0001
    Method
    		 Binomial
    Parameter type
    		 Percentage of participants with pCR
    Point estimate
    21.79
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 9.08
         upper limit
    		 34.23

    Secondary: Number of participants with overall response at Week 6

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    End point title
    		 Number of participants with overall response at Week 6
    End point description
    The number of participants with overall response (complete response and/or partial response) was evaluated using World Health Organization (WHO) criteria by clinical examination and by mammography and breast echography with bi-dimensional measurements at Week 6. As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: participants
        Overall Response
    102
    81
    45
        No Change
    33
    57
    81
        Progressive Disease
    2
    5
    11
        Not Evaluated
    12
    7
    9
        Missing Data
    3
    4
    3
    No statistical analyses for this end point

    Secondary: Overall response at the time of surgery

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    End point title
    		 Overall response at the time of surgery
    End point description
    The number of participants with overall response (complete response and/or partial response) was evaluated using WHO criteria by clinical examination and mammography and breast echography with bi-dimensional measurements at the time of surgery (Weeks 20 to 22). As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.
    End point type
    Secondary
    End point timeframe
    Time of surgery (Weeks 20 to 22)
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: participants
        Overall Response
    122
    114
    105
        No Change
    7
    8
    16
        Progressive Disease
    1
    0
    2
        Not Evaluated
    14
    19
    20
        Missing Data
    8
    13
    6
    No statistical analyses for this end point

    Secondary: Number of participants with negative lymph nodes at the time of surgery

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    End point title
    		 Number of participants with negative lymph nodes at the time of surgery
    End point description
    Participants were assessed for node-negative lymph nodes at the time of surgery. As per the pathological TNM (Tumor, Node, Metastases) classification (pTNM) of malignant tumors: pN, absence or presence and extent of regional lymph node metastasis. Node-negative (pN0) participants had no regional lymph node metastasis. Although not assessed in this measure, pT is the extent of primary tumor, and pM is the absence or presence of distant metastasis.
    End point type
    Secondary
    End point timeframe
    Time of surgery (Weeks 20 to 22)
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    137
    139
    140
    Units: participants
    100
    72
    82
    No statistical analyses for this end point

    Secondary: Number of participants with actual indicated surgery

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    End point title
    		 Number of participants with actual indicated surgery
    End point description
    Participants were assessed for the type of surgery they underwent for breast cancer. Non-conservative surgery is defined as a radical or modified radical mastectomy. Conservative surgery is comprised of a lumpectomy, a quadrantectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.
    End point type
    Secondary
    End point timeframe
    At surgery (Weeks 20 to 22)
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: participants
        Conservative
    63
    66
    58
        Non-conservative
    80
    77
    85
        Non-operable
    9
    11
    6
    No statistical analyses for this end point

    Secondary: Mean change from baseline in tumor size at Week 6 and at surgery

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    End point title
    		 Mean change from baseline in tumor size at Week 6 and at surgery
    End point description
    Mean change from baseline in tumor in tumor size. Change from baseline in tumor size was defined as tumor size at Week 6/ surgery (Weeks 20 to 22) minus tumor size at baseline. The difference in treatment arms was estimated for Lapatinib 1500 mg versus Trastuzumab 2 mg/kg and for Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg versus Trastuzumab 2 mg/kg.
    End point type
    Secondary
    End point timeframe
    Week 6 and surgery (Weeks 20 to 22)
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: millimeters
    arithmetic mean (standard deviation)
        Week 6
    -25.77 ( 19.91 )
    -20.45 ( 18.43 )
    -13.42 ( 16.44 )
        Surgery (Weeks 20 to 22)
    -43.59 ( 26.88 )
    -41.01 ( 23.81 )
    -35.47 ( 22.95 )
    No statistical analyses for this end point

    Secondary: Number of participants starting paclitaxel before completing 6 weeks of treatment with either lapatinib or trastuzumab

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    End point title
    		 Number of participants starting paclitaxel before completing 6 weeks of treatment with either lapatinib or trastuzumab
    End point description
    Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    149
    149
    146
    Units: participants
    6
    8
    12
    No statistical analyses for this end point

    Secondary: Event-free Survival (EFS) - Median clinical follow-up

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    End point title
    		 Event-free Survival (EFS) - Median clinical follow-up
    End point description
    Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.
    End point type
    Secondary
    End point timeframe
    From randomization up to approximately year 10
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: years
        median (confidence interval 95%)
    9.69 (9.55 to 9.73)
    9.60 (8.21 to 9.69)
    9.66 (9.50 to 9.72)
    No statistical analyses for this end point

    Secondary: Event-free Survival (EFS) - Events and censoring

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    End point title
    		 Event-free Survival (EFS) - Events and censoring
    End point description
    Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.
    End point type
    Secondary
    End point timeframe
    From randomization up to approximately year 10
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: Number of Participants
        Number of subjects with EFS events
    43
    47
    47
        Number of subjects censored - total
    109
    107
    102
        No. censored - follow-up ongoing
    0
    0
    0
        No. censored -follow-up ended - total
    103
    105
    99
        No. censored - f/up ended - compl. study f/up
    61
    49
    58
        No. censored - f/up ended - Lost to follow-up
    17
    20
    10
        No. cens. -f/up ended - W/d (but consent for f/u)
    3
    6
    4
        No. censored - Clinical f/up ended - Withdrew
    22
    30
    27
        Number of subjects censored - Other
    6
    2
    3
    Statistical analysis title
    		 Event-free Survival (EFS) - Events and censoring
    Comparison groups
    Lapatinib 1500 mg v Trastuzumab 2 mg/kg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.981 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.52
    Notes
    [1] - The two-sided stratified log-rank test was implemented as the score test from the Cox model.
    Statistical analysis title
    		 Event-free Survival (EFS) - Events and censoring
    Comparison groups
    Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg v Trastuzumab 2 mg/kg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.548 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.878
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.34
    Notes
    [2] - The two-sided stratified log-rank test was implemented as the score test from the Cox model.

    Secondary: Overall Survival (OS) - Median survival follow-up

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    End point title
    		 Overall Survival (OS) - Median survival follow-up
    End point description
    Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.
    End point type
    Secondary
    End point timeframe
    From randomization up to approximately year 10
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: years
        median (confidence interval 95%)
    9.70 (9.60 to 9.76)
    9.62 (8.86 to 9.67)
    9.64 (9.35 to 9.71)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - Deaths and censoring

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    End point title
    		 Overall Survival (OS) - Deaths and censoring
    End point description
    Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.
    End point type
    Secondary
    End point timeframe
    From randomization up to approximately year 10
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: Number of Participants
        Number of deaths due to any cause
    26
    31
    32
        Number of subjects censored - total
    126
    123
    117
        No. censored - Survival follow-up ongoing
    0
    0
    0
        No. censored -Survival follow-up ended - total
    120
    121
    114
        No. censored - f/up ended - Compl. f/up
    74
    59
    62
        No. censored - Survival f/up ended - Lost to f/up
    22
    27
    18
        No. censored - Survival f/up ended - Withdrew
    24
    35
    34
        Number of subjects censored - Other
    6
    2
    3
    Statistical analysis title
    		 Overall Survival (OS) - Deaths and censoring
    Comparison groups
    Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg v Trastuzumab 2 mg/kg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.379 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.788
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.34
    Notes
    [3] - The two-sided stratified log-rank test was implemented as the score test from the Cox model.
    Statistical analysis title
    		 Overall Survival (OS) - Deaths and censoring
    Comparison groups
    Lapatinib 1500 mg v Trastuzumab 2 mg/kg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.88 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.962
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.6
    Notes
    [4] - The two-sided stratified log-rank test was implemented as the score test from the Cox model.

    Secondary: Assess associations between locoregional pathological Complete Response (pCR) and Event-free Survival (EFS) - Median clinical follow-up (EFS landmark population)

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    End point title
    		 Assess associations between locoregional pathological Complete Response (pCR) and Event-free Survival (EFS) - Median clinical follow-up (EFS landmark population)
    End point description
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Clinical follow-up is the period during which the patient is monitored such that all recurrence or second primary malignancy (SPM) or contralateral breast cancer (CBC) events would be reported. Patients are considered in clinical follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death.
    End point type
    Secondary
    End point timeframe
    up to year 10
    End point values
    		 Overall pathological Complete Response (pCR) No pathological Complete Response (pCR)
    Number of subjects analysed
    410
    136
    274
    Units: years
    median (confidence interval 95%)
        Median - total in EFS landmark analysis
    9.09 (9.03 to 9.13)
    9.05 (8.86 to 9.14)
    9.11 (9.05 to 9.14)
        Median - lapatinib + trastuzumab arm(n=67,71,138)
    9.12 (8.97 to 9.15)
    9.13 (8.97 to 9.23)
    9.10 (7.24 to 9.15)
        Median - lapatinib arm (n=30,104,134)
    9.05 (8.23 to 9.12)
    8.08 (6.08 to 9.12)
    9.09 (8.52 to 9.19)
        Median - trastuzumab arm (n=39,99,138)
    9.11 (8.96 to 9.17)
    8.98 (8.38 to 9.21)
    9.12 (9.03 to 9.25)
    Statistical analysis title
    		 pCR v EFS
    Statistical analysis description
    Overall - All subjects in the EFS landmark analysis
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00079
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.481
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.73
    Statistical analysis title
    		 pCR v EFS
    Statistical analysis description
    Subjects in the EFS landmark analysis in the lapatinib + trastuzumab arm
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.004
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.71
    Statistical analysis title
    		 pCR v EFS
    Statistical analysis description
    Subjects in the EFS landmark analysis in the lapatinib arm
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.134
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.532
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 1.16
    Statistical analysis title
    		 pCR v EFS
    Statistical analysis description
    Subjects in the EFS landmark analysis in the trastuzumab arm
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.163
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.601
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.2

    Secondary: Assess associations between locoregional pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of participants with EFS events (EFS landmark population)

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    End point title
    		 Assess associations between locoregional pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of participants with EFS events (EFS landmark population)
    End point description
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. For patients who had breast cancer surgery, EFS events are post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For patients who do not undergo breast cancer surgery, EFS events are death during clinical follow-up or non-completion of any neo-adjuvant investigational product due to disease progression or second primary malignancy or contralateral breast cancer.
    End point type
    Secondary
    End point timeframe
    up to year 10
    End point values
    		 Overall pathological Complete Response (pCR) No pathological Complete Response (pCR)
    Number of subjects analysed
    410
    136
    274
    Units: Number of participants
        All subjects with EFS events
    127
    29
    98
        lapatinib + trastuzumab-w/ EFS events(n=67,71,138)
    39
    11
    28
        lapatinib-w/ EFS events (n=30,104,134)
    43
    7
    36
        trastuzumab-w/ EFS events (n=39,99,138)
    45
    11
    34
    No statistical analyses for this end point

    Secondary: Assess associations between locoregional pathological Complete Response (pCR) and and Overall Survival (OS) - Median clinical follow-up (OS landmark population)

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    End point title
    		 Assess associations between locoregional pathological Complete Response (pCR) and and Overall Survival (OS) - Median clinical follow-up (OS landmark population)
    End point description
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Patients are considered in survival follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death. For subjects with no death recorded in the database, time to death is censored.
    End point type
    Secondary
    End point timeframe
    up to year 10
    End point values
    		 pathological Complete Response (pCR) No pathological Complete Response (pCR) Overall
    Number of subjects analysed
    137
    283
    420
    Units: years
    median (confidence interval 95%)
        median - all subjects in the OS landmark analysis
    9.10 (8.97 to 9.18)
    9.09 (9.03 to 9.12)
    9.09 (9.04 to 9.13)
        median - lapatinib + trastuzumab arm (n=67,72,139)
    9.14 (9.05 to 9.24)
    9.09 (7.95 to 9.15)
    9.12 (9.05 to 9.16)
        median - lapatinib arm (n=30,109,139)
    8.31 (7.24 to 9.15)
    9.08 (8.95 to 9.14)
    9.07 (8.50 to 9.12)
        median - trastuzumab arm (n=40,102,142)
    8.98 (8.02 to 9.21)
    9.09 (8.51 to 9.15)
    9.07 (8.86 to 9.14)
    Statistical analysis title
    		 pCR v OS
    Statistical analysis description
    Overall - All subjects in the OS landmark analysis
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00041
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.366
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.63
    Statistical analysis title
    		 pCR v OS
    Statistical analysis description
    Subjects in the OS landmark analysis in the lapatinib arm
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.125
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.433
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 1.17
    Statistical analysis title
    		 pCR v OS
    Statistical analysis description
    Subjects in the OS landmark analysis in the trastuzumab arm
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.058
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.414
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1
    Statistical analysis title
    		 pCR v OS
    Statistical analysis description
    Subjects in the OS landmark analysis in the lapatinib + trastuzumab arm
    Comparison groups
    pathological Complete Response (pCR) v No pathological Complete Response (pCR)
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.002
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.223
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.58

    Secondary: Assess associations between locoregional pathological Complete Response (pCR) and and Overall Survival (OS) - Number of participants who died (OS landmark population).

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    End point title
    		 Assess associations between locoregional pathological Complete Response (pCR) and and Overall Survival (OS) - Number of participants who died (OS landmark population).
    End point description
    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Includes deaths due to any cause.
    End point type
    Secondary
    End point timeframe
    up to year 10
    End point values
    		 pathological Complete Response (pCR) No pathological Complete Response (pCR) Overall
    Number of subjects analysed
    137
    283
    420
    Units: Number of Participants
        Total No. in the OS landmark analysis who died
    15
    70
    85
        n died - lapatinib + trastuzumab arm(n=67,72,139)
    5
    19
    24
        n died - lapatinib arm (n=30,109,139)
    4
    26
    30
        n died - trastuzumab arm (n=40,102,142)
    6
    25
    31
    No statistical analyses for this end point

    Secondary: To assess safety via a comparison of the three treatment arms - to measure on-treatment primary cardiac endpoints

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    End point title
    		 To assess safety via a comparison of the three treatment arms - to measure on-treatment primary cardiac endpoints
    End point description
    End point type
    Secondary
    End point timeframe
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    149
    151
    148
    Units: Participants
    2
    0
    1
    No statistical analyses for this end point

    Secondary: Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)

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    End point title
    		 Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)
    End point description
    Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)
    End point type
    Secondary
    End point timeframe
    Week 2 and Week 6
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    25
    26
    26
    Units: Percentage of participants
    number (not applicable)
        MRR (%) Determined by PET/CT at week 2
    95.0
    66.7
    56.5
        MRR (%) Determined by PET/CT at week 6
    78.9
    60.9
    43.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with the Indicated Biomarker Expression - PIK3CA.

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    End point title
    		 Percentage of Participants with the Indicated Biomarker Expression - PIK3CA.
    End point description
    Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    119
    124
    112
    Units: Percentage of participants
    25
    23
    19
    No statistical analyses for this end point

    Secondary: Percentage of Participants with the Indicated Biomarker Expression - PTEN.

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    End point title
    		 Percentage of Participants with the Indicated Biomarker Expression - PTEN.
    End point description
    Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    112
    123
    114
    Units: Percentage of participants
        PTEN Normal (%)
    75
    74
    70
        PTEN Loss (%)
    25
    26
    30
    No statistical analyses for this end point

    Secondary: Ratio (95% CI) of geometric means in p95HER2 expression in HR positive patients with pCR vs no pCR

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    End point title
    		 Ratio (95% CI) of geometric means in p95HER2 expression in HR positive patients with pCR vs no pCR
    End point description
    Ratio (95% CI) of geometric means in p95 human epidermal growth factor receptor (p95HER2) expression in hormone-receptor (HR) positive patients with pathological complete response (pCR) vs no pCR
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    91
    97
    93
    Units: Ratio
        geometric mean (confidence interval 95%)
    2.1 (1.2 to 3.7)
    1.0 (0.50 to 1.87)
    1.6 (1.0 to 2.71)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Circulating Tumor Cells (CTC) in the Bloodstream

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    End point title
    		 Percentage of Participants with Circulating Tumor Cells (CTC) in the Bloodstream
    End point description
    Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. In the adjuvant phase, after surgery all participants received 3 courses of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide, followed by lapatinib 1500 mg or trastuzumab 2 mg/kg or lapatinib 1000/750 mg plus trastuzumab 2 mg/kg given prior to surgery in the neoadjuvant setting for an additional 34 weeks.
    End point type
    Secondary
    End point timeframe
    Measurement performed at one or more of the time points: baseline, week 2 or week 18
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    20
    19
    12
    Units: Percentage of Participants
    25
    21
    17
    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 FPFT up to 30 days after study drug discontinuation, which was approximately 31 weeks. Deaths post treatment survival follow up were collected after the on treatment period, up to 10 years.
    End point type
    Post-hoc
    End point timeframe
    on-treatment: up to week 31; post-treatment: up to year 10
    End point values
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Lapatinib 1500 mg Trastuzumab 2 mg/kg
    Number of subjects analysed
    152
    154
    149
    Units: Participants
        Total Deaths
    26
    31
    32
        On-Treatment Deaths (n=151,148,149)
    1
    2
    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 collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.
    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
    23.0
    Reporting groups
    Reporting group title
    Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
    Reporting group description
    		 Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks

    Reporting group title
    Trastuzumab 2 mg/kg
    Reporting group description
    		 Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks

    Reporting group title
    Lapatinib 1500 mg
    Reporting group description
    		 Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks

    Serious adverse events
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Trastuzumab 2 mg/kg Lapatinib 1500 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    61 / 149 (40.94%)
    36 / 148 (24.32%)
    58 / 151 (38.41%)
         number of deaths (all causes)
    1
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    LOBULAR BREAST CARCINOMA IN SITU
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    Vascular disorders
    JUGULAR VEIN THROMBOSIS
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    CHEST DISCOMFORT
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    CHEST PAIN
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    5 / 149 (3.36%)
    2 / 148 (1.35%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    METRORRHAGIA
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VULVOVAGINAL PRURITUS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 148 (0.00%)
    0 / 151 (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
    ORGANISING PNEUMONIA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    PNEUMONITIS
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         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 EMBOLISM
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         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
    ACCIDENTAL OVERDOSE
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    POISONING
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEROMA
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    TRANSFUSION REACTION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    Cardiac disorders
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    AGRANULOCYTOSIS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 149 (2.01%)
    8 / 148 (5.41%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    14 / 149 (9.40%)
    16 / 148 (10.81%)
    13 / 151 (8.61%)
         occurrences causally related to treatment / all
    5 / 20
    2 / 19
    2 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    9 / 149 (6.04%)
    0 / 148 (0.00%)
    9 / 151 (5.96%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DUODENITIS
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    ENTERITIS
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    GASTRITIS EROSIVE
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS ACUTE
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    4 / 149 (2.68%)
    0 / 148 (0.00%)
    4 / 151 (2.65%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTRANSAMINASAEMIA
         subjects affected / exposed
    15 / 149 (10.07%)
    3 / 148 (2.03%)
    23 / 151 (15.23%)
         occurrences causally related to treatment / all
    15 / 17
    3 / 3
    25 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    BLISTER
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHRECTASIA
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOPOROTIC FRACTURE
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    ROTATOR CUFF SYNDROME
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BREAST CELLULITIS
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS STAPHYLOCOCCAL
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    DEVICE RELATED INFECTION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    DEVICE RELATED SEPSIS
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    HEPATITIS B
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HERPES SIMPLEX
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    PNEUMONIA
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 148 (1.35%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VASCULAR DEVICE INFECTION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERPHOSPHATASAEMIA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (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
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg Trastuzumab 2 mg/kg Lapatinib 1500 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    147 / 149 (98.66%)
    141 / 148 (95.27%)
    148 / 151 (98.01%)
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    1 / 149 (0.67%)
    6 / 148 (4.05%)
    3 / 151 (1.99%)
         occurrences all number
    1
    6
    3
    HAEMATOMA
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    1
    HOT FLUSH
         subjects affected / exposed
    22 / 149 (14.77%)
    21 / 148 (14.19%)
    15 / 151 (9.93%)
         occurrences all number
    26
    23
    15
    HYPERTENSION
         subjects affected / exposed
    5 / 149 (3.36%)
    8 / 148 (5.41%)
    5 / 151 (3.31%)
         occurrences all number
    5
    11
    5
    HYPOTENSION
         subjects affected / exposed
    8 / 149 (5.37%)
    2 / 148 (1.35%)
    5 / 151 (3.31%)
         occurrences all number
    9
    2
    6
    LYMPHOEDEMA
         subjects affected / exposed
    3 / 149 (2.01%)
    3 / 148 (2.03%)
    5 / 151 (3.31%)
         occurrences all number
    3
    3
    5
    PHLEBITIS
         subjects affected / exposed
    2 / 149 (1.34%)
    5 / 148 (3.38%)
    3 / 151 (1.99%)
         occurrences all number
    2
    5
    3
    General disorders and administration site conditions
    AXILLARY PAIN
         subjects affected / exposed
    5 / 149 (3.36%)
    3 / 148 (2.03%)
    0 / 151 (0.00%)
         occurrences all number
    6
    4
    0
    ASTHENIA
         subjects affected / exposed
    39 / 149 (26.17%)
    35 / 148 (23.65%)
    47 / 151 (31.13%)
         occurrences all number
    55
    53
    71
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 149 (0.00%)
    6 / 148 (4.05%)
    3 / 151 (1.99%)
         occurrences all number
    0
    8
    3
    CHEST PAIN
         subjects affected / exposed
    5 / 149 (3.36%)
    6 / 148 (4.05%)
    5 / 151 (3.31%)
         occurrences all number
    5
    6
    6
    FACE OEDEMA
         subjects affected / exposed
    3 / 149 (2.01%)
    4 / 148 (2.70%)
    5 / 151 (3.31%)
         occurrences all number
    3
    4
    5
    CHILLS
         subjects affected / exposed
    11 / 149 (7.38%)
    6 / 148 (4.05%)
    3 / 151 (1.99%)
         occurrences all number
    13
    6
    3
    FATIGUE
         subjects affected / exposed
    52 / 149 (34.90%)
    38 / 148 (25.68%)
    45 / 151 (29.80%)
         occurrences all number
    81
    55
    54
    FEELING COLD
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    0
    3
    1
    GENERALISED OEDEMA
         subjects affected / exposed
    1 / 149 (0.67%)
    3 / 148 (2.03%)
    3 / 151 (1.99%)
         occurrences all number
    3
    3
    7
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    2 / 151 (1.32%)
         occurrences all number
    3
    2
    2
    MUCOSAL DRYNESS
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    2 / 151 (1.32%)
         occurrences all number
    3
    2
    2
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    36 / 149 (24.16%)
    22 / 148 (14.86%)
    34 / 151 (22.52%)
         occurrences all number
    39
    27
    38
    MUCOSAL EROSION
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences all number
    4
    0
    0
    OEDEMA
         subjects affected / exposed
    4 / 149 (2.68%)
    11 / 148 (7.43%)
    0 / 151 (0.00%)
         occurrences all number
    5
    13
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    8 / 149 (5.37%)
    13 / 148 (8.78%)
    9 / 151 (5.96%)
         occurrences all number
    10
    14
    12
    PAIN
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    6 / 151 (3.97%)
         occurrences all number
    3
    2
    7
    PERIPHERAL SWELLING
         subjects affected / exposed
    4 / 149 (2.68%)
    3 / 148 (2.03%)
    2 / 151 (1.32%)
         occurrences all number
    5
    3
    2
    PYREXIA
         subjects affected / exposed
    34 / 149 (22.82%)
    23 / 148 (15.54%)
    23 / 151 (15.23%)
         occurrences all number
    43
    28
    33
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    6 / 149 (4.03%)
    7 / 148 (4.73%)
    6 / 151 (3.97%)
         occurrences all number
    7
    8
    6
    SEASONAL ALLERGY
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    3
    0
    1
    Reproductive system and breast disorders
    AMENORRHOEA
         subjects affected / exposed
    6 / 149 (4.03%)
    1 / 148 (0.68%)
    3 / 151 (1.99%)
         occurrences all number
    7
    1
    3
    BREAST PAIN
         subjects affected / exposed
    6 / 149 (4.03%)
    15 / 148 (10.14%)
    5 / 151 (3.31%)
         occurrences all number
    6
    15
    6
    BREAST DISCHARGE
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences all number
    4
    0
    0
    MENSTRUATION IRREGULAR
         subjects affected / exposed
    1 / 149 (0.67%)
    3 / 148 (2.03%)
    2 / 151 (1.32%)
         occurrences all number
    1
    3
    2
    PELVIC PAIN
         subjects affected / exposed
    0 / 149 (0.00%)
    4 / 148 (2.70%)
    0 / 151 (0.00%)
         occurrences all number
    0
    4
    0
    VULVOVAGINAL DRYNESS
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    2 / 151 (1.32%)
         occurrences all number
    2
    3
    2
    VULVOVAGINAL INFLAMMATION
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 148 (0.00%)
    4 / 151 (2.65%)
         occurrences all number
    0
    0
    4
    VULVOVAGINAL PRURITUS
         subjects affected / exposed
    2 / 149 (1.34%)
    4 / 148 (2.70%)
    2 / 151 (1.32%)
         occurrences all number
    2
    5
    2
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    25 / 149 (16.78%)
    26 / 148 (17.57%)
    17 / 151 (11.26%)
         occurrences all number
    34
    30
    19
    DYSPNOEA
         subjects affected / exposed
    16 / 149 (10.74%)
    13 / 148 (8.78%)
    11 / 151 (7.28%)
         occurrences all number
    19
    13
    13
    DYSPHONIA
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 148 (1.35%)
    5 / 151 (3.31%)
         occurrences all number
    1
    3
    5
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    6 / 149 (4.03%)
    6 / 148 (4.05%)
    2 / 151 (1.32%)
         occurrences all number
    6
    7
    4
    EPISTAXIS
         subjects affected / exposed
    37 / 149 (24.83%)
    22 / 148 (14.86%)
    30 / 151 (19.87%)
         occurrences all number
    43
    23
    32
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 148 (2.03%)
    0 / 151 (0.00%)
         occurrences all number
    0
    4
    0
    NASAL INFLAMMATION
         subjects affected / exposed
    5 / 149 (3.36%)
    1 / 148 (0.68%)
    3 / 151 (1.99%)
         occurrences all number
    5
    1
    3
    NASAL DRYNESS
         subjects affected / exposed
    6 / 149 (4.03%)
    2 / 148 (1.35%)
    6 / 151 (3.97%)
         occurrences all number
    6
    4
    6
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    16 / 149 (10.74%)
    15 / 148 (10.14%)
    20 / 151 (13.25%)
         occurrences all number
    18
    19
    24
    PRODUCTIVE COUGH
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences all number
    3
    0
    0
    RHINORRHOEA
         subjects affected / exposed
    13 / 149 (8.72%)
    10 / 148 (6.76%)
    6 / 151 (3.97%)
         occurrences all number
    16
    12
    6
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    7 / 149 (4.70%)
    9 / 148 (6.08%)
    5 / 151 (3.31%)
         occurrences all number
    7
    9
    5
    ANXIETY
         subjects affected / exposed
    7 / 149 (4.70%)
    11 / 148 (7.43%)
    9 / 151 (5.96%)
         occurrences all number
    7
    12
    9
    INSOMNIA
         subjects affected / exposed
    34 / 149 (22.82%)
    24 / 148 (16.22%)
    23 / 151 (15.23%)
         occurrences all number
    39
    26
    26
    SLEEP DISORDER
         subjects affected / exposed
    5 / 149 (3.36%)
    2 / 148 (1.35%)
    4 / 151 (2.65%)
         occurrences all number
    8
    3
    4
    Investigations
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    6 / 149 (4.03%)
    4 / 148 (2.70%)
    2 / 151 (1.32%)
         occurrences all number
    9
    4
    2
    GAMMA-GLUTAMYLTRANSFERASE
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 148 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    4
    0
    3
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    7 / 151 (4.64%)
         occurrences all number
    3
    1
    9
    NEUTROPHIL COUNT INCREASED
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences all number
    4
    4
    1
    WEIGHT INCREASED
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    2 / 151 (1.32%)
         occurrences all number
    2
    3
    2
    WEIGHT DECREASED
         subjects affected / exposed
    8 / 149 (5.37%)
    1 / 148 (0.68%)
    10 / 151 (6.62%)
         occurrences all number
    8
    1
    11
    Injury, poisoning and procedural complications
    RADIATION SKIN INJURY
         subjects affected / exposed
    16 / 149 (10.74%)
    18 / 148 (12.16%)
    11 / 151 (7.28%)
         occurrences all number
    17
    19
    11
    SEROMA
         subjects affected / exposed
    2 / 149 (1.34%)
    6 / 148 (4.05%)
    0 / 151 (0.00%)
         occurrences all number
    2
    6
    0
    THERMAL BURN
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences all number
    3
    1
    0
    WOUND COMPLICATION
         subjects affected / exposed
    4 / 149 (2.68%)
    6 / 148 (4.05%)
    4 / 151 (2.65%)
         occurrences all number
    5
    6
    4
    Cardiac disorders
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences all number
    4
    1
    0
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    4 / 149 (2.68%)
    2 / 148 (1.35%)
    0 / 151 (0.00%)
         occurrences all number
    6
    2
    0
    PALPITATIONS
         subjects affected / exposed
    6 / 149 (4.03%)
    3 / 148 (2.03%)
    6 / 151 (3.97%)
         occurrences all number
    8
    3
    6
    TACHYCARDIA
         subjects affected / exposed
    4 / 149 (2.68%)
    4 / 148 (2.70%)
    2 / 151 (1.32%)
         occurrences all number
    4
    4
    2
    Nervous system disorders
    AGEUSIA
         subjects affected / exposed
    4 / 149 (2.68%)
    0 / 148 (0.00%)
    3 / 151 (1.99%)
         occurrences all number
    7
    0
    5
    DIZZINESS
         subjects affected / exposed
    13 / 149 (8.72%)
    15 / 148 (10.14%)
    13 / 151 (8.61%)
         occurrences all number
    13
    19
    17
    DYSGEUSIA
         subjects affected / exposed
    6 / 149 (4.03%)
    1 / 148 (0.68%)
    6 / 151 (3.97%)
         occurrences all number
    10
    1
    6
    HEADACHE
         subjects affected / exposed
    31 / 149 (20.81%)
    26 / 148 (17.57%)
    27 / 151 (17.88%)
         occurrences all number
    43
    33
    31
    HYPOAESTHESIA
         subjects affected / exposed
    9 / 149 (6.04%)
    12 / 148 (8.11%)
    7 / 151 (4.64%)
         occurrences all number
    11
    14
    7
    MEMORY IMPAIRMENT
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 148 (1.35%)
    4 / 151 (2.65%)
         occurrences all number
    2
    4
    4
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    19 / 149 (12.75%)
    19 / 148 (12.84%)
    21 / 151 (13.91%)
         occurrences all number
    22
    21
    22
    NEUROTOXICITY
         subjects affected / exposed
    3 / 149 (2.01%)
    3 / 148 (2.03%)
    6 / 151 (3.97%)
         occurrences all number
    5
    3
    6
    PARAESTHESIA
         subjects affected / exposed
    24 / 149 (16.11%)
    22 / 148 (14.86%)
    15 / 151 (9.93%)
         occurrences all number
    25
    26
    16
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    13 / 149 (8.72%)
    14 / 148 (9.46%)
    19 / 151 (12.58%)
         occurrences all number
    15
    15
    22
    POLYNEUROPATHY
         subjects affected / exposed
    5 / 149 (3.36%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    7
    3
    2
    TASTE DISORDER
         subjects affected / exposed
    9 / 149 (6.04%)
    1 / 148 (0.68%)
    6 / 151 (3.97%)
         occurrences all number
    9
    1
    8
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    36 / 149 (24.16%)
    27 / 148 (18.24%)
    33 / 151 (21.85%)
         occurrences all number
    44
    35
    47
    LEUKOPENIA
         subjects affected / exposed
    21 / 149 (14.09%)
    10 / 148 (6.76%)
    18 / 151 (11.92%)
         occurrences all number
    32
    15
    28
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences all number
    3
    1
    0
    NEUTROPENIA
         subjects affected / exposed
    47 / 149 (31.54%)
    37 / 148 (25.00%)
    51 / 151 (33.77%)
         occurrences all number
    66
    48
    91
    LYMPHOPENIA
         subjects affected / exposed
    5 / 149 (3.36%)
    6 / 148 (4.05%)
    2 / 151 (1.32%)
         occurrences all number
    7
    7
    5
    THROMBOCYTOPENIA
         subjects affected / exposed
    4 / 149 (2.68%)
    1 / 148 (0.68%)
    2 / 151 (1.32%)
         occurrences all number
    4
    1
    2
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    1
    TINNITUS
         subjects affected / exposed
    6 / 149 (4.03%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    6
    3
    1
    VERTIGO
         subjects affected / exposed
    11 / 149 (7.38%)
    6 / 148 (4.05%)
    7 / 151 (4.64%)
         occurrences all number
    11
    7
    8
    Eye disorders
    DRY EYE
         subjects affected / exposed
    4 / 149 (2.68%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences all number
    5
    2
    1
    LACRIMATION INCREASED
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    3 / 151 (1.99%)
         occurrences all number
    4
    1
    3
    VISUAL IMPAIRMENT
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    2 / 151 (1.32%)
         occurrences all number
    2
    4
    2
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    3 / 149 (2.01%)
    4 / 148 (2.70%)
    1 / 151 (0.66%)
         occurrences all number
    3
    4
    1
    ABDOMINAL DISTENSION
         subjects affected / exposed
    10 / 149 (6.71%)
    5 / 148 (3.38%)
    8 / 151 (5.30%)
         occurrences all number
    12
    6
    9
    ABDOMINAL PAIN
         subjects affected / exposed
    21 / 149 (14.09%)
    13 / 148 (8.78%)
    28 / 151 (18.54%)
         occurrences all number
    28
    16
    36
    ANAL INFLAMMATION
         subjects affected / exposed
    4 / 149 (2.68%)
    1 / 148 (0.68%)
    2 / 151 (1.32%)
         occurrences all number
    5
    1
    2
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    23 / 149 (15.44%)
    16 / 148 (10.81%)
    27 / 151 (17.88%)
         occurrences all number
    32
    18
    31
    CONSTIPATION
         subjects affected / exposed
    18 / 149 (12.08%)
    15 / 148 (10.14%)
    15 / 151 (9.93%)
         occurrences all number
    23
    19
    19
    DRY MOUTH
         subjects affected / exposed
    9 / 149 (6.04%)
    3 / 148 (2.03%)
    5 / 151 (3.31%)
         occurrences all number
    10
    3
    5
    DIARRHOEA
         subjects affected / exposed
    128 / 149 (85.91%)
    52 / 148 (35.14%)
    123 / 151 (81.46%)
         occurrences all number
    296
    79
    238
    DYSPEPSIA
         subjects affected / exposed
    17 / 149 (11.41%)
    10 / 148 (6.76%)
    26 / 151 (17.22%)
         occurrences all number
    20
    11
    30
    DYSPHAGIA
         subjects affected / exposed
    3 / 149 (2.01%)
    3 / 148 (2.03%)
    0 / 151 (0.00%)
         occurrences all number
    3
    3
    0
    EPIGASTRIC DISCOMFORT
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    2 / 151 (1.32%)
         occurrences all number
    4
    2
    2
    FLATULENCE
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    5 / 151 (3.31%)
         occurrences all number
    3
    2
    6
    GASTRITIS
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    8 / 151 (5.30%)
         occurrences all number
    2
    3
    8
    HAEMORRHOIDS
         subjects affected / exposed
    13 / 149 (8.72%)
    10 / 148 (6.76%)
    10 / 151 (6.62%)
         occurrences all number
    13
    12
    10
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    5 / 149 (3.36%)
    0 / 148 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    5
    0
    2
    MOUTH ULCERATION
         subjects affected / exposed
    12 / 149 (8.05%)
    1 / 148 (0.68%)
    4 / 151 (2.65%)
         occurrences all number
    16
    1
    6
    NAUSEA
         subjects affected / exposed
    75 / 149 (50.34%)
    76 / 148 (51.35%)
    81 / 151 (53.64%)
         occurrences all number
    140
    111
    152
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    4 / 149 (2.68%)
    0 / 148 (0.00%)
    2 / 151 (1.32%)
         occurrences all number
    4
    0
    2
    STOMATITIS
         subjects affected / exposed
    27 / 149 (18.12%)
    23 / 148 (15.54%)
    18 / 151 (11.92%)
         occurrences all number
    39
    25
    29
    TOOTHACHE
         subjects affected / exposed
    4 / 149 (2.68%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences all number
    4
    2
    1
    VOMITING
         subjects affected / exposed
    54 / 149 (36.24%)
    38 / 148 (25.68%)
    57 / 151 (37.75%)
         occurrences all number
    96
    57
    93
    Hepatobiliary disorders
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    21 / 149 (14.09%)
    7 / 148 (4.73%)
    26 / 151 (17.22%)
         occurrences all number
    24
    8
    33
    HYPERTRANSAMINASAEMIA
         subjects affected / exposed
    55 / 149 (36.91%)
    39 / 148 (26.35%)
    55 / 151 (36.42%)
         occurrences all number
    113
    106
    112
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    22 / 149 (14.77%)
    5 / 148 (3.38%)
    20 / 151 (13.25%)
         occurrences all number
    28
    7
    25
    ALOPECIA
         subjects affected / exposed
    95 / 149 (63.76%)
    96 / 148 (64.86%)
    90 / 151 (59.60%)
         occurrences all number
    101
    103
    97
    DERMATITIS
         subjects affected / exposed
    13 / 149 (8.72%)
    8 / 148 (5.41%)
    13 / 151 (8.61%)
         occurrences all number
    13
    11
    13
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    14 / 149 (9.40%)
    4 / 148 (2.70%)
    12 / 151 (7.95%)
         occurrences all number
    18
    4
    16
    DRY SKIN
         subjects affected / exposed
    28 / 149 (18.79%)
    8 / 148 (5.41%)
    29 / 151 (19.21%)
         occurrences all number
    28
    8
    30
    ECZEMA
         subjects affected / exposed
    6 / 149 (4.03%)
    2 / 148 (1.35%)
    4 / 151 (2.65%)
         occurrences all number
    6
    2
    4
    ERYTHEMA
         subjects affected / exposed
    14 / 149 (9.40%)
    15 / 148 (10.14%)
    14 / 151 (9.27%)
         occurrences all number
    15
    16
    18
    EXFOLIATIVE RASH
         subjects affected / exposed
    8 / 149 (5.37%)
    0 / 148 (0.00%)
    4 / 151 (2.65%)
         occurrences all number
    9
    0
    4
    HYPERHIDROSIS
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    2
    3
    1
    NAIL DISORDER
         subjects affected / exposed
    36 / 149 (24.16%)
    18 / 148 (12.16%)
    26 / 151 (17.22%)
         occurrences all number
    44
    20
    32
    NAIL DYSTROPHY
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    2 / 151 (1.32%)
         occurrences all number
    3
    1
    2
    ONYCHOLYSIS
         subjects affected / exposed
    7 / 149 (4.70%)
    2 / 148 (1.35%)
    0 / 151 (0.00%)
         occurrences all number
    7
    2
    0
    ONYCHALGIA
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    3 / 151 (1.99%)
         occurrences all number
    3
    1
    3
    PAIN OF SKIN
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 148 (1.35%)
    4 / 151 (2.65%)
         occurrences all number
    1
    2
    4
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    14 / 149 (9.40%)
    3 / 148 (2.03%)
    14 / 151 (9.27%)
         occurrences all number
    16
    3
    15
    PRURITUS
         subjects affected / exposed
    24 / 149 (16.11%)
    9 / 148 (6.08%)
    29 / 151 (19.21%)
         occurrences all number
    32
    10
    33
    RASH
         subjects affected / exposed
    67 / 149 (44.97%)
    28 / 148 (18.92%)
    68 / 151 (45.03%)
         occurrences all number
    94
    34
    93
    RASH PRURITIC
         subjects affected / exposed
    4 / 149 (2.68%)
    3 / 148 (2.03%)
    3 / 151 (1.99%)
         occurrences all number
    4
    4
    4
    SCAR PAIN
         subjects affected / exposed
    1 / 149 (0.67%)
    4 / 148 (2.70%)
    3 / 151 (1.99%)
         occurrences all number
    1
    4
    3
    SKIN EXFOLIATION
         subjects affected / exposed
    4 / 149 (2.68%)
    1 / 148 (0.68%)
    0 / 151 (0.00%)
         occurrences all number
    4
    1
    0
    SKIN FISSURES
         subjects affected / exposed
    13 / 149 (8.72%)
    4 / 148 (2.70%)
    4 / 151 (2.65%)
         occurrences all number
    17
    4
    5
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    6 / 149 (4.03%)
    2 / 148 (1.35%)
    6 / 151 (3.97%)
         occurrences all number
    7
    2
    6
    SKIN IRRITATION
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    1
    SKIN LESION
         subjects affected / exposed
    5 / 149 (3.36%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    6
    0
    1
    SKIN REACTION
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 148 (0.00%)
    4 / 151 (2.65%)
         occurrences all number
    3
    0
    4
    Renal and urinary disorders
    DYSURIA
         subjects affected / exposed
    11 / 149 (7.38%)
    5 / 148 (3.38%)
    6 / 151 (3.97%)
         occurrences all number
    12
    6
    7
    HAEMATURIA
         subjects affected / exposed
    4 / 149 (2.68%)
    0 / 148 (0.00%)
    0 / 151 (0.00%)
         occurrences all number
    4
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    27 / 149 (18.12%)
    32 / 148 (21.62%)
    26 / 151 (17.22%)
         occurrences all number
    31
    38
    31
    BACK PAIN
         subjects affected / exposed
    22 / 149 (14.77%)
    14 / 148 (9.46%)
    10 / 151 (6.62%)
         occurrences all number
    25
    15
    11
    BONE PAIN
         subjects affected / exposed
    10 / 149 (6.71%)
    18 / 148 (12.16%)
    12 / 151 (7.95%)
         occurrences all number
    13
    21
    12
    JOINT STIFFNESS
         subjects affected / exposed
    2 / 149 (1.34%)
    4 / 148 (2.70%)
    1 / 151 (0.66%)
         occurrences all number
    2
    4
    1
    MUSCLE SPASMS
         subjects affected / exposed
    6 / 149 (4.03%)
    3 / 148 (2.03%)
    4 / 151 (2.65%)
         occurrences all number
    7
    4
    5
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    4 / 149 (2.68%)
    1 / 148 (0.68%)
    2 / 151 (1.32%)
         occurrences all number
    4
    1
    2
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    8 / 149 (5.37%)
    11 / 148 (7.43%)
    16 / 151 (10.60%)
         occurrences all number
    9
    12
    20
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    1 / 149 (0.67%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    1
    3
    1
    MYALGIA
         subjects affected / exposed
    31 / 149 (20.81%)
    34 / 148 (22.97%)
    33 / 151 (21.85%)
         occurrences all number
    52
    50
    50
    NECK PAIN
         subjects affected / exposed
    7 / 149 (4.70%)
    5 / 148 (3.38%)
    5 / 151 (3.31%)
         occurrences all number
    7
    5
    7
    OSTEOPOROSIS
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    0
    3
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    13 / 149 (8.72%)
    13 / 148 (8.78%)
    20 / 151 (13.25%)
         occurrences all number
    18
    16
    25
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    5 / 151 (3.31%)
         occurrences all number
    2
    3
    6
    CONJUNCTIVITIS
         subjects affected / exposed
    11 / 149 (7.38%)
    5 / 148 (3.38%)
    8 / 151 (5.30%)
         occurrences all number
    13
    5
    8
    HERPES SIMPLEX
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    0 / 151 (0.00%)
         occurrences all number
    3
    2
    0
    CYSTITIS
         subjects affected / exposed
    8 / 149 (5.37%)
    3 / 148 (2.03%)
    6 / 151 (3.97%)
         occurrences all number
    8
    3
    6
    INFLUENZA
         subjects affected / exposed
    8 / 149 (5.37%)
    9 / 148 (6.08%)
    8 / 151 (5.30%)
         occurrences all number
    9
    10
    8
    LOCALISED INFECTION
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 148 (0.00%)
    3 / 151 (1.99%)
         occurrences all number
    3
    0
    4
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    1
    MASTITIS
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    2
    3
    1
    NAIL INFECTION
         subjects affected / exposed
    8 / 149 (5.37%)
    0 / 148 (0.00%)
    1 / 151 (0.66%)
         occurrences all number
    9
    0
    2
    NASOPHARYNGITIS
         subjects affected / exposed
    11 / 149 (7.38%)
    11 / 148 (7.43%)
    12 / 151 (7.95%)
         occurrences all number
    15
    11
    13
    ORAL HERPES
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 148 (2.03%)
    0 / 151 (0.00%)
         occurrences all number
    2
    3
    0
    PARONYCHIA
         subjects affected / exposed
    17 / 149 (11.41%)
    2 / 148 (1.35%)
    14 / 151 (9.27%)
         occurrences all number
    22
    2
    22
    PHARYNGITIS
         subjects affected / exposed
    4 / 149 (2.68%)
    5 / 148 (3.38%)
    7 / 151 (4.64%)
         occurrences all number
    4
    5
    7
    RHINITIS
         subjects affected / exposed
    6 / 149 (4.03%)
    5 / 148 (3.38%)
    4 / 151 (2.65%)
         occurrences all number
    6
    5
    4
    PUSTULE
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 148 (0.68%)
    1 / 151 (0.66%)
         occurrences all number
    3
    1
    2
    SKIN INFECTION
         subjects affected / exposed
    4 / 149 (2.68%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences all number
    4
    2
    1
    SINUSITIS
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 148 (1.35%)
    5 / 151 (3.31%)
         occurrences all number
    3
    2
    5
    TONSILLITIS
         subjects affected / exposed
    0 / 149 (0.00%)
    4 / 148 (2.70%)
    3 / 151 (1.99%)
         occurrences all number
    0
    4
    4
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    10 / 149 (6.71%)
    14 / 148 (9.46%)
    9 / 151 (5.96%)
         occurrences all number
    12
    16
    10
    URINARY TRACT INFECTION
         subjects affected / exposed
    11 / 149 (7.38%)
    6 / 148 (4.05%)
    14 / 151 (9.27%)
         occurrences all number
    11
    6
    16
    VAGINAL INFECTION
         subjects affected / exposed
    5 / 149 (3.36%)
    2 / 148 (1.35%)
    1 / 151 (0.66%)
         occurrences all number
    5
    2
    1
    VIRAL INFECTION
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 148 (2.03%)
    0 / 151 (0.00%)
         occurrences all number
    0
    3
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    35 / 149 (23.49%)
    17 / 148 (11.49%)
    39 / 151 (25.83%)
         occurrences all number
    57
    21
    50
    DEHYDRATION
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 148 (0.00%)
    5 / 151 (3.31%)
         occurrences all number
    2
    0
    6
    HYPERGLYCAEMIA
         subjects affected / exposed
    3 / 149 (2.01%)
    4 / 148 (2.70%)
    0 / 151 (0.00%)
         occurrences all number
    3
    4
    0
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 148 (2.03%)
    1 / 151 (0.66%)
         occurrences all number
    0
    3
    1
    HYPERPHOSPHATASAEMIA
         subjects affected / exposed
    22 / 149 (14.77%)
    12 / 148 (8.11%)
    22 / 151 (14.57%)
         occurrences all number
    30
    18
    29
    HYPOKALAEMIA
         subjects affected / exposed
    4 / 149 (2.68%)
    0 / 148 (0.00%)
    3 / 151 (1.99%)
         occurrences all number
    4
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2008
    Amendment No. 01
    10 Oct 2008
    Amendment No. 02
    17 May 2013
    Amendment No. 03
    13 May 2016
    Amendment No. 04
    24 Aug 2016
    Amendment No. 05

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

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