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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study Comparing GW572016 and Letrozole versus Letrozole in Subjects with Estrogen/Progesterone Receptor- Positive Advanced or Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2004-003928-35
    Trial protocol
    		 IT  
    Global end of trial date
    22 Mar 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Apr 2021
    First version publication date
    04 Apr 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    EGF30008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00073528
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Novartis: CLAP016A2308
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, 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
    22 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate and compare progression free survival (PFS) in subjects with Estrogen/Progesterone Receptor- Positive (ER+/PgR+), human epidermal growth factor receptor 2-positive (ErbB2+) advanced or metastatic breast cancer treated with GW572016 (lapatinib) and letrozole, versus letrozole and placebo.
    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
    09 Dec 2013
    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: 13
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Canada: 29
    Country: Number of subjects enrolled
    Chile: 18
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Czechia: 20
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    France: 130
    Country: Number of subjects enrolled
    Germany: 104
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Ireland: 53
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Pakistan: 30
    Country: Number of subjects enrolled
    Peru: 47
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    Russian Federation: 89
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Spain: 77
    Country: Number of subjects enrolled
    Tunisia: 16
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United Kingdom: 84
    Country: Number of subjects enrolled
    United States: 325
    Worldwide total number of subjects
    1286
    EEA total number of subjects
    550
    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)
    709
    From 65 to 84 years
    559
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted at 212 centers in 29 countries (Argentina, Australia, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Italy, Republic of Korea, Mexico, Netherlands, New Zealand, Pakistan, Peru, Poland, Russian Federation, South-Africa, Spain, Tunisia, Turkey, UK, USA).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Letrozole 2.5 mg
    Arm description
    		 Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg once daily orally

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lapatinib matching placebo 1500 mg once daily orally

    Arm title
    		 Lapatinib 1500 mg + Letrozole 2.5 mg
    Arm description
    		 Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mg once daily orally

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg once daily orally

    Number of subjects in period 1
    		Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Started
    644
    642
    Completed
    14
    14
    Not completed
    630
    628
         Adverse event, serious fatal
    488
    473
         Consent withdrawn by subject
    50
    45
         Study terminated by Sponsor
    10
    29
         Not Specified
    18
    19
         Unknown
    9
    12
         Lost to follow-up
    52
    45
         Protocol deviation
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Letrozole 2.5 mg
    Reporting group description
    		 Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.

    Reporting group title
    Lapatinib 1500 mg + Letrozole 2.5 mg
    Reporting group description
    		 Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.

    Reporting group values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg Total
    Number of subjects
    		 644 642 1286
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 352 357 709
        From 65-84 years
    		 280 279 559
        85 years and over
    		 12 6 18
    Sex: Female, Male
    Units:
        Female
    		 644 642 1286
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 557 529 1086
        Black
    		 10 17 27
        Asian
    		 30 30 60
        American Hispanic
    		 44 57 101
        Other
    		 3 9 12
    AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.3 ± 9.95 62.8 ± 9.70 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Letrozole 2.5 mg
    Reporting group description
    		 Participants received 6 tablets of placebo, identical in appearance to lapatinib tablets, orally daily (approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 milligrams (mg) orally daily, preferably with the daily dose of lapatinib.

    Reporting group title
    Lapatinib 1500 mg + Letrozole 2.5 mg
    Reporting group description
    		 Participants received 6 tablets of Lapatinib orally daily (250 mg lapatinib/tablet for a total of 1500 mg of lapatinib/day; approximately at the same time each day), either 1 hour (or more) before breakfast or 1 hour (or more) after breakfast. Participants also received 1 tablet of letrozole 2.5 mg orally daily, preferably with the daily dose of lapatinib.

    Primary: Number of participants with progression free survival (PFS) in the human epidermal growth factor receptor 2 (HER2)-Positive advanced or metastatic breast cancer as assessed by the Investigator

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    End point title
    		 Number of participants with progression free survival (PFS) in the human epidermal growth factor receptor 2 (HER2)-Positive advanced or metastatic breast cancer as assessed by the Investigator
    End point description
    PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. The date of documented PD is defined as the date of radiological PD as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0), PD is defined as a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of the first documented progression or date of death from any cause, whichever came first, assessed for up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: Participants
    89
    88
    Statistical analysis title
    		 Number of participants with PFS in HER2+
    Comparison groups
    Placebo + Letrozole 2.5 mg v Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.019 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.96
    Notes
    [1] - p-value is from stratified log-rank test, stratifying for site of disease and time since prior adjuvant endocrine therapy at screening

    Primary: Progression free survival (PFS) of participants in the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Progression free survival (PFS) of participants in the HER2-Positive Population as assessed by the Investigator
    End point description
    PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
    End point type
    Primary
    End point timeframe
    From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    89
    88
    Units: Weeks
        median (confidence interval 95%)
    13.0 (12.0 to 23.7)
    35.4 (24.1 to 39.4)
    Statistical analysis title
    		 PFS of participants in the HER2-Positive
    Comparison groups
    Placebo + Letrozole 2.5 mg v Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.019 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.96
    Notes
    [2] - p-value is from stratified log-rank test, stratifying for site of disease and time since prior adjuvant endocrine therapy at screening

    Secondary: Number of participants with PFS in the Intent-To-Treat (ITT) Population as assessed by the Investigator

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    End point title
    		 Number of participants with PFS in the Intent-To-Treat (ITT) Population as assessed by the Investigator
    End point description
    PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: Participants
    476
    413
    No statistical analyses for this end point

    Secondary: PFS in participants in the ITT Population as assessed by the Investigator

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    End point title
    		 PFS in participants in the ITT Population as assessed by the Investigator
    End point description
    PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. The date of documented disease progression is defined as the date of radiological disease progression as assessed by the investigator based on imaging data and also by the clinical assessment of symptomatic progression. Per RECIST 1.0, disease progression is defined as a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started, or the appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    476
    413
    Units: Weeks
        median (confidence interval 95%)
    47.0 (36.9 to 50.9)
    51.7 (47.6 to 59.6)
    No statistical analyses for this end point

    Secondary: Overall survival in the HER2-Positive Population

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    End point title
    		 Overall survival in the HER2-Positive Population
    End point description
    Overall survival was defined as the time from randomization until death due to any cause.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of death due to any cause, assessed up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: Weeks
        median (confidence interval 95%)
    140.3 (92.1 to 159.4)
    144.7 (95.6 to 999)
    No statistical analyses for this end point

    Secondary: Overall tumor response (OR) for participants with measurable and non-measurable disease, including bone scans, in the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Overall tumor response (OR) for participants with measurable and non-measurable disease, including bone scans, in the HER2-Positive Population as assessed by the Investigator
    End point description
    OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 * (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: Percent response rate
        number (confidence interval 95%)
    14.8 (8.7 to 22.9)
    27.9 (19.8 to 37.2)
    No statistical analyses for this end point

    Secondary: Number of participants with overall tumor response (OR) by stratification factors with measurable disease, including bone scans, in the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Number of participants with overall tumor response (OR) by stratification factors with measurable disease, including bone scans, in the HER2-Positive Population as assessed by the Investigator
    End point description
    Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval [DI] =>6 months or DI <6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT to the randomization date.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    75
    93
    Units: Participants
        SDS, Soft tissue or visceral
    14
    31
        SDS, Bone-only disease
    0
    0
        PAET, DI =>6 months
    12
    24
        PAET, DI <6 months
    2
    7
    No statistical analyses for this end point

    Secondary: Clinical benefit (CB) in the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Clinical benefit (CB) in the HER2-Positive Population as assessed by the Investigator
    End point description
    CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: Months
        number (confidence interval 95%)
    28.7 (20.4 to 38.2)
    47.7 (38.2 to 57.4)
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated best response from the participants with measurable and non-measurable disease, including bone scans, in the HER2-Positive Population as assessed by the Investigator.

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    End point title
    		 Number of participants with the indicated best response from the participants with measurable and non-measurable disease, including bone scans, in the HER2-Positive Population as assessed by the Investigator.
    End point description
    CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: Participants
        CR
    4
    5
        PR
    12
    26
        SD
    35
    44
        PD
    49
    30
        Unknown
    8
    6
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated best response from the participants with measurable and non-measurable disease, including bone scans, in the ITT Population as assessed by the Investigator.

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    End point title
    		 Number of participants with the indicated best response from the participants with measurable and non-measurable disease, including bone scans, in the ITT Population as assessed by the Investigator.
    End point description
    CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as a reference the smallest sum LD since the baseline measurement. The best overall response is defined as the best response recorded from the start of treatment until disease progression/recurrence. PD: presence of target lesions, non-target lesions, and/or new lesions.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: Participants
        CR
    26
    28
        PR
    153
    168
        SD
    243
    280
        PD
    174
    113
        Unknown
    48
    53
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated time to response for CR or PR in the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Number of participants with the indicated time to response for CR or PR in the HER2-Positive Population as assessed by the Investigator
    End point description
    Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    16
    31
    Units: Participants
        Week 12
    11
    23
        Week 16
    1
    3
        Week 24 or longer
    4
    5
    No statistical analyses for this end point

    Secondary: Duration of response for the participants with CR or PR in the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Duration of response for the participants with CR or PR in the HER2-Positive Population as assessed by the Investigator
    End point description
    Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    16
    31
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    84.4 (29.1 to 999)
    47.4 (25.1 to 108.0)
    No statistical analyses for this end point

    Secondary: Number of participants with evidence of brain metastases in the HER2-Positive Population

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    End point title
    		 Number of participants with evidence of brain metastases in the HER2-Positive Population
    End point description
    The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: participants
    2
    1
    No statistical analyses for this end point

    Secondary: Time to progression (TTP) for the HER2-Positive Population as assessed by the Investigator

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    End point title
    		 Time to progression (TTP) for the HER2-Positive Population as assessed by the Investigator
    End point description
    TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    89
    87
    Units: weeks
        median (confidence interval 95%)
    13.0 (12.0 to 23.7)
    35.4 (24.1 to 39.4)
    No statistical analyses for this end point

    Secondary: Overall survival in the ITT Population

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    End point title
    		 Overall survival in the ITT Population
    End point description
    Overall survival was defined as the time from randomization until death due to any cause.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of death due to any cause, assessed up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    234
    240
    Units: weeks
        median (confidence interval 95%)
    176.3 (156.1 to 189.7)
    170.9 (157.7 to 196.3)
    No statistical analyses for this end point

    Secondary: Overall tumor response (OR) for participants with measurable and non-measurable disease, including bone scans, in the ITT Population as assessed by the Investigator

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    End point title
    		 Overall tumor response (OR) for participants with measurable and non-measurable disease, including bone scans, in the ITT Population as assessed by the Investigator
    End point description
    OR is defined as the percentage of participants achieving either a confirmed complete response (CR) or partial response (PR). Response was assessed via Response Evaluation criteria in Solid Tumors (RECIST). The percentage of participants with response was calculated by using the formula: 100 * (number of participants with CR + number of participants with PR)/total number of participants. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: percentage of participants
        number (not applicable)
    27.8
    30.5
    No statistical analyses for this end point

    Secondary: Number of participants with overall tumor response (OR) by stratification factors with measurable disease, including bone scans, in the ITT Population as assessed by the Investigator

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    End point title
    		 Number of participants with overall tumor response (OR) by stratification factors with measurable disease, including bone scans, in the ITT Population as assessed by the Investigator
    End point description
    Participants were stratified based on site of disease at screening (SDS) (soft tissue or visceral or bone-only disease) and prior adjuvant endocrine therapy (PAET) (discontinuation interval [DI] =>6 months or DI <6 months). OR is defined as the number of participants achieving either a confirmed CR or PR. Response was assessed via RECIST. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. DI is defined as the time period from stopping the PEAT and the randomization date.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    486
    480
    Units: participants
        SDS, Soft tissue or visceral
    170
    190
        PAET, DI =>6 months
    151
    168
        PAET, DI <6 months
    19
    22
    No statistical analyses for this end point

    Secondary: Clinical benefit (CB) in the ITT Population as assessed by the Investigator

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    End point title
    		 Clinical benefit (CB) in the ITT Population as assessed by the Investigator
    End point description
    CB is defined as the percentage of participants with evidence of confirmed CR, PR, or stable disease (SD) for at least 6 months. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the baseline measurement.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: percentage of participants
        number (not applicable)
    50.6
    55.8
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated time to response for CR or PR in the ITT Population as assessed by the Investigator

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    End point title
    		 Number of participants with the indicated time to response for CR or PR in the ITT Population as assessed by the Investigator
    End point description
    Time to response is defined as the time from randomization until the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sume of the LD of target lesions, taking as reference the baseline sum LD) (whichever status was recorded first). The assessments of CR or PR required confirmation using bone scans.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    179
    196
    Units: participants
        Week 12
    76
    94
        Week 16
    21
    18
        Week 24
    28
    28
        Week 28
    17
    14
        Week 36 or longer
    37
    42
    No statistical analyses for this end point

    Secondary: Duration of response for the participants with CR or PR in the ITT Population as assessed by the Investigator

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    End point title
    		 Duration of response for the participants with CR or PR in the ITT Population as assessed by the Investigator
    End point description
    Duration of response is defined as the time from the first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the LD of target lesions, taking as a reference the baseline sum LD) until the first documented sign of disease progression or death due to any cause. The assessments of CR or PR required confirmation using bone scans.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    179
    196
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    72.6 (39.1 to 145.7)
    60.1 (36.0 to 138.9)
    No statistical analyses for this end point

    Secondary: Number of participants with evidence of brain metastases from the ITT Population

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    End point title
    		 Number of participants with evidence of brain metastases from the ITT Population
    End point description
    The confirmation criteria for the evidence of brain metastases was the incidence of lesions occurring within any part of the central nervous system (CNS) as evidenced by radiological scans. Metastases are defined as the spread of cancer from one part of the body to another.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: participants
    4
    6
    No statistical analyses for this end point

    Secondary: TTP for participants from the ITT Population as assessed by the Investigator

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    End point title
    		 TTP for participants from the ITT Population as assessed by the Investigator
    End point description
    TTP is defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer. Disease progression was based on the assessments by the Investigator.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    469
    409
    Units: weeks
        median (confidence interval 95%)
    47.0 (36.9 to 50.9)
    51.7 (47.6 to 59.6)
    No statistical analyses for this end point

    Secondary: Number of participants completing the functional assessment of cancer therapy-breast (FACT-B) questionnaire at the scheduled visits

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    End point title
    		 Number of participants completing the functional assessment of cancer therapy-breast (FACT-B) questionnaire at the scheduled visits
    End point description
    Quality of Life (QOL) was assessed using the FACT-B questionnaire, which was a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales (each ranging from 0 [not at all] to 4 [very much]) indicate a higher QOL. The score is transformed for FACT-B and results in a total score ranging from 0 to 144. Complete: completing at least 1 question from FACT-B.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) visit; Week 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, and 192 visits; conclusion/withdrawal visit
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: Participants
        Day 1, baseline
    605
    605
        Week 12
    460
    476
        Week 24
    350
    382
        Week 36
    291
    294
        Week 48
    254
    243
        Week 60
    199
    183
        Week 72
    181
    153
        Week 84
    144
    119
        Week 96
    117
    98
        Week 108
    80
    62
        Week 120
    59
    56
        Week 132
    43
    43
        Week 144
    33
    33
        Week 156
    22
    21
        Week 168
    15
    11
        Week 180
    11
    5
        Week 192
    6
    1
        Conclusion/withdrawal
    327
    359
    No statistical analyses for this end point

    Secondary: Adjusted mean change from baseline for the FACT-B total score using observed data

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    End point title
    		 Adjusted mean change from baseline for the FACT-B total score using observed data
    End point description
    Quality of Life (QOL) was assessed using the FACT-B questionnaire, which is a 37-item (27 general and 10 breast cancer-specific questions) self-reporting instrument consisting of 5 dimensions: physical-, social/family-, emotional-, functional-well being, and a breast cancer subscale. Higher scores on the FACT-B scales indicate a higher QOL; each ranging from 0 (not at all) to 4 (very much). The score is transformed for FACT-B and results in a total score ranging from 0 to 144. The FACT-B is designed to measure multidimensional QOL in participants with breast cancer.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    61
    78
    Units: Adjusted mean change
    number (not applicable)
        Week 12
    1.5
    3.3
        Week 24
    3.8
    1.9
        Week 36
    3.3
    1.4
        Week 48
    2.9
    0.3
        Conclusion/WD
    -9.4
    -9.0
    No statistical analyses for this end point

    Secondary: Adjusted mean change from baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) score using observed data

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    End point title
    		 Adjusted mean change from baseline for the Functional Assessment of Cancer Therapy-General (FACT-G) score using observed data
    End point description
    FACT-G is a subscale of the FACT-B QOL questionnaire and consists of 27 questions grouped into 4 domains that measure a participant's physical, functional, social and family, and emotional well-being. FACT-G is assessed on a five-point Likert-type scale, with scores ranging from 0 to 4 (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). The total score is calculated as the sum of the item scores on the subscale; the total ranges from 0 to 108, with higher score indicating a better quality of life.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    63
    79
    Units: Adjusted mean change
    number (not applicable)
        Week 12
    1.6
    1.5
        Week 24
    2.2
    0.6
        Week 36
    2.6
    0.9
        Week 48
    2.0
    -0.9
        Conclusion/WD
    -7.8
    -8.5
    No statistical analyses for this end point

    Secondary: Adjusted mean change from baseline for the trial outcome index (TOI) score using observed data

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    End point title
    		 Adjusted mean change from baseline for the trial outcome index (TOI) score using observed data
    End point description
    The TOI score is the sum of the physical well-being, functional well-being, and breast cancer unweighted subscale scores. The total TOI score ranges from 0 to 92, with higher scores representing a better quality of life.
    End point type
    Secondary
    End point timeframe
    Week 12, 24, 36, and 48 visits; conclusion/withdrawal visit
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    62
    77
    Units: Adjusted mean change
    number (not applicable)
        Week 12
    -0.3
    2.7
        Week 24
    3.9
    2.0
        Week 36
    3.3
    0.8
        Week 48
    2.2
    -0.7
        Conclusion/WD
    -6.2
    -6.4
    No statistical analyses for this end point

    Secondary: Number of participants classified as QOL responders based on the FACT-B, FACT-G, and TOI total scores

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    End point title
    		 Number of participants classified as QOL responders based on the FACT-B, FACT-G, and TOI total scores
    End point description
    A minimally important difference (MID) is the smallest difference in a score for a measure of QOL that corresponds to a difference in function or clinical course. Responders are defined as participants with an MID => 8 for the FACT-B score, and an MID =>6 for the FACT-G and TOI scores.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    87
    99
    Units: Participants
        FACT-B total, =>8 (MID upper bound)
    29
    33
        FACT-G, =>6 (MID upper bound)
    29
    38
        TOI, =>6 (MID upper bound)
    29
    33
    No statistical analyses for this end point

    Secondary: Number of participants with clinical benefit categorized by HER2 fluorescence in situ hybridization (FISH) status

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    End point title
    		 Number of participants with clinical benefit categorized by HER2 fluorescence in situ hybridization (FISH) status
    End point description
    Clinical benefit: participants with CR, PR, or SD for =>6-month period. FISH testing measures the amount of the HER2 gene in each cell. This gene is responsible for the overproduction of the HER2 protein. FISH-positive: excessive amounts of the gene are present; FISH-negative: normal levels of the gene are present.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: Participants
        FISH status, Positive
    28
    49
        FISH status, Negative
    237
    245
        FISH status, missing
    61
    64
    No statistical analyses for this end point

    Secondary: Number of participants with clinical benefit categorized by HER2 ImmunoHistoChemistry (IHC) intensity

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    End point title
    		 Number of participants with clinical benefit categorized by HER2 ImmunoHistoChemistry (IHC) intensity
    End point description
    IHC is a commonly used test to assess the amount of the HER2 receptor protein on the surface of the cancer cells. The IHC test results in a score of 0 to 3+, which indicates the amount of HER2 receptor protein on the cells in a sample of breast cancer tissue. Tissue scores of 0 to 1+ indicate HER2 negativity; scores of 2+ and 3+ indicate HER2 positivity. Clinical benefit is defined as participants with CR, PR, or SD for =>6-month period.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: Participants
        IHC Intensity 0
    74
    106
        IHC Intensity 1
    108
    106
        IHC Intensity 2
    94
    85
        IHC Intensity 3
    16
    26
        IHC Intensity Missing
    34
    35
    No statistical analyses for this end point

    Secondary: Number of participants with response in participants with baseline serum HER2 extracellular domain (ECD) baseline values greater than 15 nanograms per milliliter (ng/mL) and 15 ng/mL or lower

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    End point title
    		 Number of participants with response in participants with baseline serum HER2 extracellular domain (ECD) baseline values greater than 15 nanograms per milliliter (ng/mL) and 15 ng/mL or lower
    End point description
    The HER2 ECD is a glycoprotein that can be shed from the cell surface into the blood of normal individuals and can be elevated in different pathologic conditions. The serum HER2 ECD level generally reflects the tissue HER2 status. The HER2 ECD is quantified in serum with an enzyme-linked immunosorbent assay (ELISA). Non-Evaluable (NE): any participant who could not be classified as CR, PR, SD, or PD.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    108
    111
    Units: Participants
        >15 ng/mL, CR/PR
    3
    9
        >15 ng/mL, SD
    11
    13
        >15 ng/mL, PD/NE
    39
    12
        =<15 ng/mL, CR/PR
    12
    17
        =<15 ng/mL, SD
    23
    30
        =<15 ng/mL, PD/NE
    16
    23
    No statistical analyses for this end point

    Secondary: Number of HER2-Negative participants at baseline with and without seroconversion to a status of HER2 Positive

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    End point title
    		 Number of HER2-Negative participants at baseline with and without seroconversion to a status of HER2 Positive
    End point description
    Participants who had a HER2-negative tumor status based on baseline tissue with baseline serum HER2 ECD values =<15 ng/mL but later had at least two consecutive serum HER2 ECD values >15 ng/mL experienced seroconversion.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    474
    478
    Units: Participants
        Seroconversion, No
    323
    140
        Seroconversion, Yes
    52
    219
        Missing
    99
    119
    No statistical analyses for this end point

    Secondary: Time to seroconversion for participants who were HER2 Negative at baseline but became HER2 Positive

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    End point title
    		 Time to seroconversion for participants who were HER2 Negative at baseline but became HER2 Positive
    End point description
    Time to seroconversion was defined as the time from the date of randomization until the first instance of serum HER2 (>15 ng/mL) on two consecutive occasions.
    End point type
    Secondary
    End point timeframe
    Up to 46 months
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    52
    219
    Units: Weeks
        median (confidence interval 95%)
    999 (999 to 999)
    36.1 (24.0 to 48.9)
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated expression of tumor by epidermal growth factor receptor (ErbB1/HER1/EGFR) at baseline

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    End point title
    		 Number of participants with the indicated expression of tumor by epidermal growth factor receptor (ErbB1/HER1/EGFR) at baseline
    End point description
    EGFR is a cell surface receptor tyrosine kinase expressed in certain types of tumors. Depending upon the staining intensity, EGFR was graded as follows: 0=absence of membrane staining above background in all tumor cells; EGFR-positive=staining is defined as any IHC staining of tumor cell membranes above background level, whether it is complete or incomplete circumferential staining (1+, 2+, 3+).
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    644
    642
    Units: Participants
        EGFR, 0
    513
    522
        EGFR, 1+
    43
    45
        EGFR, 2+
    17
    12
        EGFR, 3+
    3
    1
    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, for a maximum duration of 663.9 weeks (treatment duration ranged from 0.1 to 659.9 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 14 years. Patients who didn’t die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
    End point type
    Post-hoc
    End point timeframe
    up to 663 weeks (on-treatment), up to approximately 14 years (study duration)
    End point values
    		 Placebo + Letrozole 2.5 mg Lapatinib 1500 mg + Letrozole 2.5 mg
    Number of subjects analysed
    507
    506
    Units: Participants
        On-treatment deaths
    23
    18
        All deaths
    484
    488
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    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
    20.1
    Reporting groups
    Reporting group title
    Placebo + Letrozole 2.5mg
    Reporting group description
    		 Placebo + Letrozole 2.5mg

    Reporting group title
    Lapatinib 1500mg + Letrozole 2.5mg
    Reporting group description
    		 Lapatinib 1500mg + Letrozole 2.5mg

    Serious adverse events
    		 Placebo + Letrozole 2.5mg Lapatinib 1500mg + Letrozole 2.5mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 624 (16.51%)
    150 / 654 (22.94%)
         number of deaths (all causes)
    23
    18
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphoma
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 624 (0.32%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 624 (0.16%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lymphoedema
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 624 (0.16%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 624 (0.48%)
    4 / 654 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 624 (0.32%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 624 (0.64%)
    4 / 654 (0.61%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Crohn's disease
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast abscess
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian enlargement
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 624 (0.16%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 624 (0.48%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    8 / 624 (1.28%)
    17 / 654 (2.60%)
         occurrences causally related to treatment / all
    7 / 8
    16 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental poisoning
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    2 / 624 (0.32%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Synovial rupture
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine perforation
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 624 (0.32%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 624 (0.32%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 624 (0.80%)
    6 / 654 (0.92%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 624 (0.16%)
    7 / 654 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    3 / 624 (0.48%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 624 (0.16%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 624 (0.32%)
    5 / 654 (0.76%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 624 (0.00%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye injury
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 624 (0.48%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 624 (0.00%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 624 (0.32%)
    15 / 654 (2.29%)
         occurrences causally related to treatment / all
    1 / 2
    11 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 624 (0.64%)
    5 / 654 (0.76%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis haemorrhagic
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 624 (1.12%)
    9 / 654 (1.38%)
         occurrences causally related to treatment / all
    3 / 7
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder pain
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    0 / 624 (0.00%)
    5 / 654 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Excessive granulation tissue
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site cellulitis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatorenal failure
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 624 (0.16%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Carcinoid tumour
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ankle fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    7 / 624 (1.12%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 624 (0.16%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatinaemia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 624 (0.32%)
    4 / 654 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    4 / 624 (0.64%)
    3 / 654 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 624 (0.32%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tooth abscess
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 624 (0.16%)
    6 / 654 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 624 (0.32%)
    7 / 654 (1.07%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 624 (0.16%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 624 (0.00%)
    2 / 654 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 624 (0.16%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 624 (0.32%)
    0 / 654 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 624 (0.00%)
    1 / 654 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Letrozole 2.5mg Lapatinib 1500mg + Letrozole 2.5mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    481 / 624 (77.08%)
    589 / 654 (90.06%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    28 / 624 (4.49%)
    58 / 654 (8.87%)
         occurrences all number
    33
    81
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 624 (3.85%)
    54 / 654 (8.26%)
         occurrences all number
    28
    75
    Blood alkaline phosphatase increased
         subjects affected / exposed
    15 / 624 (2.40%)
    34 / 654 (5.20%)
         occurrences all number
    18
    49
    Weight decreased
         subjects affected / exposed
    13 / 624 (2.08%)
    35 / 654 (5.35%)
         occurrences all number
    14
    40
    Vascular disorders
    Hot flush
         subjects affected / exposed
    80 / 624 (12.82%)
    65 / 654 (9.94%)
         occurrences all number
    94
    73
    Cardiac disorders
    Dyspnoea
         subjects affected / exposed
    68 / 624 (10.90%)
    58 / 654 (8.87%)
         occurrences all number
    83
    71
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    46 / 624 (7.37%)
    44 / 654 (6.73%)
         occurrences all number
    56
    53
    Headache
         subjects affected / exposed
    79 / 624 (12.66%)
    84 / 654 (12.84%)
         occurrences all number
    114
    126
    Insomnia
         subjects affected / exposed
    50 / 624 (8.01%)
    41 / 654 (6.27%)
         occurrences all number
    60
    52
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 624 (4.49%)
    52 / 654 (7.95%)
         occurrences all number
    35
    74
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    62 / 624 (9.94%)
    76 / 654 (11.62%)
         occurrences all number
    88
    112
    Decreased appetite
         subjects affected / exposed
    55 / 624 (8.81%)
    80 / 654 (12.23%)
         occurrences all number
    65
    95
    Fatigue
         subjects affected / exposed
    98 / 624 (15.71%)
    124 / 654 (18.96%)
         occurrences all number
    121
    169
    Mucosal inflammation
         subjects affected / exposed
    11 / 624 (1.76%)
    37 / 654 (5.66%)
         occurrences all number
    20
    45
    Pyrexia
         subjects affected / exposed
    32 / 624 (5.13%)
    42 / 654 (6.42%)
         occurrences all number
    42
    54
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    28 / 624 (4.49%)
    48 / 654 (7.34%)
         occurrences all number
    36
    52
    Abdominal pain upper
         subjects affected / exposed
    16 / 624 (2.56%)
    36 / 654 (5.50%)
         occurrences all number
    17
    41
    Constipation
         subjects affected / exposed
    64 / 624 (10.26%)
    45 / 654 (6.88%)
         occurrences all number
    81
    49
    Diarrhoea
         subjects affected / exposed
    109 / 624 (17.47%)
    393 / 654 (60.09%)
         occurrences all number
    148
    784
    Dyspepsia
         subjects affected / exposed
    28 / 624 (4.49%)
    56 / 654 (8.56%)
         occurrences all number
    46
    71
    Nausea
         subjects affected / exposed
    123 / 624 (19.71%)
    190 / 654 (29.05%)
         occurrences all number
    162
    274
    Stomatitis
         subjects affected / exposed
    8 / 624 (1.28%)
    34 / 654 (5.20%)
         occurrences all number
    8
    41
    Vomiting
         subjects affected / exposed
    69 / 624 (11.06%)
    101 / 654 (15.44%)
         occurrences all number
    89
    138
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    89 / 624 (14.26%)
    71 / 654 (10.86%)
         occurrences all number
    116
    92
    Epistaxis
         subjects affected / exposed
    9 / 624 (1.44%)
    61 / 654 (9.33%)
         occurrences all number
    10
    88
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 624 (0.64%)
    39 / 654 (5.96%)
         occurrences all number
    4
    53
    Alopecia
         subjects affected / exposed
    39 / 624 (6.25%)
    74 / 654 (11.31%)
         occurrences all number
    40
    77
    Dry skin
         subjects affected / exposed
    25 / 624 (4.01%)
    82 / 654 (12.54%)
         occurrences all number
    26
    94
    Erythema
         subjects affected / exposed
    9 / 624 (1.44%)
    33 / 654 (5.05%)
         occurrences all number
    13
    39
    Nail disorder
         subjects affected / exposed
    6 / 624 (0.96%)
    63 / 654 (9.63%)
         occurrences all number
    6
    79
    Paronychia
         subjects affected / exposed
    1 / 624 (0.16%)
    39 / 654 (5.96%)
         occurrences all number
    1
    64
    Pruritus
         subjects affected / exposed
    50 / 624 (8.01%)
    76 / 654 (11.62%)
         occurrences all number
    58
    112
    Rash
         subjects affected / exposed
    56 / 624 (8.97%)
    223 / 654 (34.10%)
         occurrences all number
    68
    338
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    135 / 624 (21.63%)
    112 / 654 (17.13%)
         occurrences all number
    184
    176
    Back pain
         subjects affected / exposed
    91 / 624 (14.58%)
    99 / 654 (15.14%)
         occurrences all number
    110
    118
    Bone pain
         subjects affected / exposed
    48 / 624 (7.69%)
    26 / 654 (3.98%)
         occurrences all number
    59
    29
    Muscle spasms
         subjects affected / exposed
    22 / 624 (3.53%)
    33 / 654 (5.05%)
         occurrences all number
    23
    42
    Musculoskeletal chest pain
         subjects affected / exposed
    34 / 624 (5.45%)
    30 / 654 (4.59%)
         occurrences all number
    35
    34
    Musculoskeletal pain
         subjects affected / exposed
    49 / 624 (7.85%)
    52 / 654 (7.95%)
         occurrences all number
    63
    60
    Myalgia
         subjects affected / exposed
    41 / 624 (6.57%)
    26 / 654 (3.98%)
         occurrences all number
    53
    31
    Pain in extremity
         subjects affected / exposed
    65 / 624 (10.42%)
    67 / 654 (10.24%)
         occurrences all number
    85
    87
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    44 / 624 (7.05%)
    50 / 654 (7.65%)
         occurrences all number
    54
    61
    Upper respiratory tract infection
         subjects affected / exposed
    32 / 624 (5.13%)
    31 / 654 (4.74%)
         occurrences all number
    38
    43
    Urinary tract infection
         subjects affected / exposed
    44 / 624 (7.05%)
    35 / 654 (5.35%)
         occurrences all number
    58
    45
    Metabolism and nutrition disorders
    Oedema peripheral
         subjects affected / exposed
    46 / 624 (7.37%)
    28 / 654 (4.28%)
         occurrences all number
    51
    40

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2004
    Amendment 1 was issued to provide further clarification to study design and update relevant sections to reflect current clinical practice.
    11 Jan 2005
    Amendment 2 was a country specific amendment for Italy. This amendment was for the pharmacogenetic research to be conducted on blood samples collected from consenting subjects as part of study EGF30008 and complied with the “Italian Proposed Guideline for the Evaluation of Pharmacogenetic Research.”
    27 Oct 2005
    Amendment 3 was issued to: revise the eligibility criteria to include only those subjects with Stage IV disease, remove Interim Analysis and add an extension to the study to include additional subjects to ensure adequate power to see a difference in both the original population as well as ErbB2-positive population.
    31 Oct 2007
    Amendment 4 was issued to: revise the statistical analysis plan for the primary endpoint, provide further clarification on the data collection and to decrease the frequency of visits for subjects that had reached 108 Weeks on study treatment.
    27 May 2008
    Amendment 5 was issued to: update the safety monitoring for hepatic events and refine ITT and modified populations.
    11 Jun 2013
    Amendment 6 was a country specific amendment for France. Protocol updated to include the Diarrhea Management Guidelines and Dermatological Assessment Guidelines.
    13 Apr 2015
    Amendment 7 was issued to allow subjects currently on study treatment to continue access to treatment with alteration to study/clinical assessments. Subject assessments and disease management were performed as indicated by local medical standard of care and local approved labeling for lapatinib and letrozole. All subjects in overall survival follow up were permitted to withdraw from the study. Subjects might be withdrawn from EGF30008 study treatment, and continue therapy via alternative means such as commercial availability and local approved labelling for this indication.
    03 Oct 2016
    Amendment 8 was issue to: delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. Administrative changes were made to align with Novartis processes and procedures. References to the source of investigational product supply were changed from non-commercial to commercial supply.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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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