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    Clinical Trial Results:
    A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination with Trastuzumab and Paclitaxel, as First Line Therapy in Women with HER2 Positive Locally Advanced or Metastatic Breast Cancer (BOLERO-1) 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.novfor complete trial results.

    Summary
    EudraCT number
    		 2008-006556-21
    Trial protocol
    		 DE   GB   FR   IT   IE   BE   GR  
    Global end of trial date
    23 Oct 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Dec 2018
    First version publication date
    08 Nov 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Changed Sponsor name to Novartis Pharma, AG from Novartis Pharmaceuticals

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001J2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00876395
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acronym: BOLERO-1
    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
    23 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The two primary objectives were to compare PFS between the combination treatment of everolimus, trastuzumab, paclitaxel, and the combination treatment of placebo, trastuzumab, paclitaxel in patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer (MBC) in the:  Full population, and  Hormone receptor (HR)-negative subpopulation
    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
    10 Sep 2009
    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: 29
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 155
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Egypt: 22
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hong Kong: 19
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Japan: 45
    Country: Number of subjects enrolled
    Korea, Republic of: 35
    Country: Number of subjects enrolled
    Lebanon: 2
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Peru: 29
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    South Africa: 28
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Taiwan: 43
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 2
    Worldwide total number of subjects
    719
    EEA total number of subjects
    113
    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)
    595
    From 65 to 84 years
    122
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 717 patients were planned to be randomized. A total of 719 patients were randomized between 10-Sep-2009 and 16-Dec-2012. Not completed reasons = primary reasons for end of treatment

    Pre-assignment
    Screening details
    		 717 patients were planned to be randomized. A total of 719 patients were randomized between 10-Sep-2009 and 16-Dec-2012. Not completed reasons = primary reasons for end of treatment

    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
    		 Everolimus + Paclitaxel + Trastuzumab
    Arm description
    		 Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    trastuzumab 2 mg/kg weekly according to the Investigator country guidelines.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m2 weekly according to the Investigator country guidelines.

    Arm title
    		 Placebo + Paclitaxel + Trastuzumab
    Arm description
    		 Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22
    Arm type
    		 Placebo

    Investigational medicinal product name
    Everolimus Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus Placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m2 weekly according to the Investigator country guidelines.

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    trastuzumab 2 mg/kg weekly according to the Investigator country guidelines.

    Number of subjects in period 1
    		Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Started
    480
    239
    Untreated
    8
    1
    Completed
    0
    0
    Not completed
    480
    239
         Adverse event, serious fatal
    12
    -
         Consent withdrawn by subject
    66
    33
         Disease progression
    259
    162
         Adverse event, non-fatal
    63
    11
         New cancer therapy
    25
    7
         Administrative problems
    39
    23
         Untreated
    8
    1
         Lost to follow-up
    2
    -
         Abnormal test procedure result(s)
    1
    -
         Protocol deviation
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus + Paclitaxel + Trastuzumab
    Reporting group description
    		 Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22

    Reporting group title
    Placebo + Paclitaxel + Trastuzumab
    Reporting group description
    		 Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22

    Reporting group values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab Total
    Number of subjects
    		 480 239 719
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 399 196 595
        From 65-84 years
    		 79 43 122
        85 years and over
    		 2 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 53.4 ( 11.46 ) 52.1 ( 11.63 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 480 239 719
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 214 97 311
        Black
    		 26 12 38
        Asian
    		 198 105 303
        Native American
    		 3 0 3
        Other
    		 39 25 64

    End points

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    End points reporting groups
    Reporting group title
    Everolimus + Paclitaxel + Trastuzumab
    Reporting group description
    		 Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22

    Reporting group title
    Placebo + Paclitaxel + Trastuzumab
    Reporting group description
    		 Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22

    Subject analysis set title
    Everolimus 10 mg/day
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Everolimus 10 mg daily

    Subject analysis set title
    Everolimus 5 mg/day
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Everolimus 5 mg daily

    Subject analysis set title
    Everolimus
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Everolimus 10 mg/day

    Subject analysis set title
    Everolimus Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo of everolimus 10 mg daily

    Subject analysis set title
    Everolimus + trastuzumab
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Everolimus plus trastuzumab

    Subject analysis set title
    Everolimus Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo of everolimus 10 mg daily

    Primary: Progression-free Survival (PFS) per Investigators’ assessment based on local radiology review - Full population

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    End point title
    		 Progression-free Survival (PFS) per Investigators’ assessment based on local radiology review - Full population
    End point description
    PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population.
    End point type
    Primary
    End point timeframe
    date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: months
        median (confidence interval 95%)
    14.95 (14.55 to 17.91)
    14.49 (12.29 to 17.08)
    Statistical analysis title
    		 Drug vs. Pbo for PFS (FP)
    Comparison groups
    Everolimus + Paclitaxel + Trastuzumab v Placebo + Paclitaxel + Trastuzumab
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1166
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.08

    Primary: Progression-free Survival (PFS) per Investigators’ assessment based on local radiology review - (hormone receptor (HR)-negative population

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    End point title
    		 Progression-free Survival (PFS) per Investigators’ assessment based on local radiology review - (hormone receptor (HR)-negative population
    End point description
    PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population.
    End point type
    Primary
    End point timeframe
    date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: Months
        median (confidence interval 95%)
    20.27 (14.95 to 24.08)
    13.08 (10.05 to 16.56)
    Statistical analysis title
    		 Drug vs. Pbo for PFS (HR- pop.)
    Comparison groups
    Everolimus + Paclitaxel + Trastuzumab v Placebo + Paclitaxel + Trastuzumab
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0049
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.91

    Secondary: Overall Survival (OS) - Full Population

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    End point title
    		 Overall Survival (OS) - Full Population
    End point description
    OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population.
    End point type
    Secondary
    End point timeframe
    up to about 76 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: Months
        median (confidence interval 95%)
    48.56 (40.94 to 58.94)
    49.97 (40.84 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - HR-negative population

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    End point title
    		 Overall Survival (OS) - HR-negative population
    End point description
    OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population.
    End point type
    Secondary
    End point timeframe
    up to about 76 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: Months
        median (confidence interval 95%)
    56.97 (44.09 to 999)
    41.63 (34.83 to 999)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) - Full Population

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    End point title
    		 Overall response rate (ORR) - Full Population
    End point description
    ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: Percentage of participants
        number (confidence interval 95%)
    67.1 (62.7 to 71.3)
    69.0 (62.8 to 74.8)
    Statistical analysis title
    		 Drug vs. Pbo for ORR (FP)
    Comparison groups
    Everolimus + Paclitaxel + Trastuzumab v Placebo + Paclitaxel + Trastuzumab
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7276
    Method
    		 Exact Cochran-Mantel-Haenzel chi-square
    Confidence interval

    Secondary: Overall response rate (ORR) - HR-negative population

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    End point title
    		 Overall response rate (ORR) - HR-negative population
    End point description
    ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: Percentage of participants
        number (confidence interval 95%)
    73.1 (66.5 to 79.0)
    70.9 (61.1 to 79.4)
    Statistical analysis title
    		 Drug vs. Pbo for ORR (HR- pop.)
    Comparison groups
    Everolimus + Paclitaxel + Trastuzumab v Placebo + Paclitaxel + Trastuzumab
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4085
    Method
    		 Exact Cochran-Mantel-Haenzel chi-square
    Confidence interval

    Secondary: Clinical benefit rate (CBR) equal to or greater than 24 weeks - Full Population

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    End point title
    		 Clinical benefit rate (CBR) equal to or greater than 24 weeks - Full Population
    End point description
    CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: Percentage of participants
        number (confidence interval 95%)
    75.8 (71.7 to 79.6)
    81.2 (75.6 to 85.9)
    Statistical analysis title
    		 Drug vs. Pbo for CBR (FP)
    Comparison groups
    Everolimus + Paclitaxel + Trastuzumab v Placebo + Paclitaxel + Trastuzumab
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9573
    Method
    		 Exact Cochran-Mantel-Haenzel chi-square
    Confidence interval

    Secondary: Clinical benefit rate (CBR) equal to or greater than 24 weeks - HR-negative Population

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    End point title
    		 Clinical benefit rate (CBR) equal to or greater than 24 weeks - HR-negative Population
    End point description
    CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: Percentage of participants
        number (confidence interval 95%)
    78.8 (72.7 to 84.2)
    79.6 (70.5 to 86.9)
    Statistical analysis title
    		 Drug vs. Pbo for CBR (HR- pop.)
    Comparison groups
    Everolimus + Paclitaxel + Trastuzumab v Placebo + Paclitaxel + Trastuzumab
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6382
    Method
    		 Exact Cochran-Mantel-Haenzel chi-square
    Confidence interval

    Secondary: Time to overall response based on Investigator - Full Population

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    End point title
    		 Time to overall response based on Investigator - Full Population
    End point description
    Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: months
        median (confidence interval 95%)
    2.10 (2.00 to 3.58)
    2.00 (1.94 to 2.27)
    No statistical analyses for this end point

    Secondary: Time to overall response based on Investigator - HR-negative Population

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    End point title
    		 Time to overall response based on Investigator - HR-negative Population
    End point description
    Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: months
        median (confidence interval 95%)
    1.94 (1.87 to 2.00)
    1.97 (1.87 to 3.58)
    No statistical analyses for this end point

    Secondary: Overall Response (OR) - Full Population

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    End point title
    		 Overall Response (OR) - Full Population
    End point description
    OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: Percentage of participants
    number (not applicable)
        Complete Response (CR)|
    5.6
    5.9
        Partial Response (PR)|
    61.5
    63.2
    No statistical analyses for this end point

    Secondary: Overall Response (OR) - HR-negative Population

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    End point title
    		 Overall Response (OR) - HR-negative Population
    End point description
    OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
    End point type
    Secondary
    End point timeframe
    up to about 23 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: Percentage of participants
    number (not applicable)
        Complete Response (CR)|
    7.7
    2.9
        Partial Response (PR)|
    65.4
    68.0
    No statistical analyses for this end point

    Secondary: Everolimus blood level concentrations at steady states for everolimus

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    End point title
    		 Everolimus blood level concentrations at steady states for everolimus
    End point description
    Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Cycle = 28 days
    End point type
    Secondary
    End point timeframe
    predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22
    End point values
    		 Everolimus 10 mg/day Everolimus 5 mg/day
    Number of subjects analysed
    60 [1]
    21 [2]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-dose (Cmin) @ C2D1|
    14.380 ( 10.0169 )
    7.959 ( 8.1546 )
        2 hours post administration (C2h) @ C2D1|
    44.485 ( 22.1986 )
    23.449 ( 10.4112 )
        Pre-dose (Cmin) @ C2D15|
    13.206 ( 9.9821 )
    5.473 ( 3.9690 )
        2 hours post administration (C2h) @ C2D15|
    43.494 ( 21.5940 )
    20.329 ( 7.9518 )
        Pre-dose (Cmin) @ C2D22|
    13.432 ( 13.2782 )
    7.494 ( 5.8503 )
        2 hours post administration (C2h) @ C2D22|
    43.947 ( 28.0107 )
    22.192 ( 10.9277 )
    Notes
    [1] - n for all categories for this arm = (54, 60, 44, 44, 44, 40, 48)
    [2] - n for all categories for this arm = (14, 17, 17, 21, 17, 21)
    No statistical analyses for this end point

    Secondary: Paclitaxel plasma concentrations

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    End point title
    		 Paclitaxel plasma concentrations
    End point description
    Blood levels at steady states for everolimus/placebo
    End point type
    Secondary
    End point timeframe
    Cycle 2/Day 15 (Pre-infusion and end of infusion)
    End point values
    		 Everolimus Everolimus Placebo
    Number of subjects analysed
    91 [3]
    43 [4]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-infusion (Cmin) @ C2D15|
    1.424 ( 5.8645 )
    0 ( 0 )
        End of infusion (Cmax) @ C2D15|
    5159.338 ( 15473.636 )
    4296.697 ( 7431.0799 )
    Notes
    [3] - n = (91, 65)
    [4] - n = (43, 33)
    No statistical analyses for this end point

    Secondary: Trastuzumab serum concentrations

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    End point title
    		 Trastuzumab serum concentrations
    End point description
    Blood levels at steady states for everolimus/placebo
    End point type
    Secondary
    End point timeframe
    Cycle 4/Day 1 (Pre-infusion and end of infusion)
    End point values
    		 Everolimus + trastuzumab Everolimus Placebo
    Number of subjects analysed
    98 [5]
    54 [6]
    Units: microgram/ml
    arithmetic mean (standard deviation)
        Pre-infusion (Cmin) @ C4D1|
    26.606 ( 9.6548 )
    29.180 ( 12.1252 )
        End of infusion (Cmax) @ C4D1|
    64.296 ( 23.4635 )
    67.643 ( 20.8852 )
    Notes
    [5] - n = (98, 83)
    [6] - n = (54, 46)
    No statistical analyses for this end point

    Secondary: Time to deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score - Full Population

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    End point title
    		 Time to deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score - Full Population
    End point description
    Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
    End point type
    Secondary
    End point timeframe
    up to about 56 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    480
    239
    Units: months
        median (confidence interval 95%)
    39.20 (31.31 to 999)
    99 (30.39 to 999)
    No statistical analyses for this end point

    Secondary: Time to deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score - HR-negative Population

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    End point title
    		 Time to deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score - HR-negative Population
    End point description
    Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
    End point type
    Secondary
    End point timeframe
    up to about 56 months
    End point values
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Number of subjects analysed
    208
    103
    Units: months
        median (confidence interval 95%)
    999 (25.56 to 999)
    999 (26.91 to 999)
    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 reported in this record are from date of First Patient First Treatment until 30 days after 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
    Everolimus + Paclitaxel + Trastuzumab
    Reporting group description
    		 Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and... more trastuzumab 2mg/kg weekly on days 1, 8, 15, 22

    Reporting group title
    Placebo + Paclitaxel + Trastuzumab
    Reporting group description
    		 Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15... more and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22

    Serious adverse events
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    173 / 472 (36.65%)
    40 / 238 (16.81%)
         number of deaths (all causes)
    23
    2
         number of deaths resulting from adverse events
    6
    0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calcinosis
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site related reaction
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (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 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    12 / 472 (2.54%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    5 / 13
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast ulceration
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         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 respiratory failure
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    12 / 472 (2.54%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    6 / 12
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    7 / 472 (1.48%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    21 / 472 (4.45%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    20 / 21
    0 / 0
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 472 (1.06%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 472 (0.64%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (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
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 472 (0.21%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 472 (0.21%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral artery embolism
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 472 (1.06%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 472 (0.64%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 472 (0.42%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 472 (1.27%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    8 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 472 (0.85%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 472 (0.42%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 472 (0.85%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ocular surface disease
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strabismus
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (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
    2 / 472 (0.42%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 472 (1.06%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 472 (0.21%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    10 / 472 (2.12%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 472 (0.42%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ulcer
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 472 (0.85%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 472 (0.42%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatinaemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (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
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 472 (0.00%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 472 (0.21%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 472 (1.06%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    4 / 8
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    10 / 472 (2.12%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    4 / 10
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 472 (0.21%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (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
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 472 (0.21%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    22 / 472 (4.66%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    11 / 22
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculoma
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 472 (0.21%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 472 (1.06%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdiaphragmatic abscess
         subjects affected / exposed
    0 / 472 (0.00%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 472 (0.85%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 472 (0.42%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 472 (1.48%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    7 / 472 (1.48%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    6 / 472 (1.27%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (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
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    3 / 472 (0.64%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 472 (0.21%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus + Paclitaxel + Trastuzumab Placebo + Paclitaxel + Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    466 / 472 (98.73%)
    236 / 238 (99.16%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    13 / 472 (2.75%)
    12 / 238 (5.04%)
         occurrences all number
    14
    12
    Hypertension
         subjects affected / exposed
    74 / 472 (15.68%)
    27 / 238 (11.34%)
         occurrences all number
    113
    50
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    94 / 472 (19.92%)
    41 / 238 (17.23%)
         occurrences all number
    176
    65
    Fatigue
         subjects affected / exposed
    168 / 472 (35.59%)
    87 / 238 (36.55%)
         occurrences all number
    262
    171
    Chills
         subjects affected / exposed
    29 / 472 (6.14%)
    6 / 238 (2.52%)
         occurrences all number
    37
    7
    Oedema peripheral
         subjects affected / exposed
    156 / 472 (33.05%)
    59 / 238 (24.79%)
         occurrences all number
    261
    82
    Peripheral swelling
         subjects affected / exposed
    30 / 472 (6.36%)
    10 / 238 (4.20%)
         occurrences all number
    40
    15
    Pain
         subjects affected / exposed
    28 / 472 (5.93%)
    12 / 238 (5.04%)
         occurrences all number
    37
    12
    Pyrexia
         subjects affected / exposed
    181 / 472 (38.35%)
    63 / 238 (26.47%)
         occurrences all number
    367
    90
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    26 / 472 (5.51%)
    12 / 238 (5.04%)
         occurrences all number
    32
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    191 / 472 (40.47%)
    80 / 238 (33.61%)
         occurrences all number
    341
    131
    Dysphonia
         subjects affected / exposed
    22 / 472 (4.66%)
    14 / 238 (5.88%)
         occurrences all number
    28
    14
    Dyspnoea
         subjects affected / exposed
    110 / 472 (23.31%)
    24 / 238 (10.08%)
         occurrences all number
    143
    35
    Epistaxis
         subjects affected / exposed
    156 / 472 (33.05%)
    43 / 238 (18.07%)
         occurrences all number
    303
    74
    Pneumonitis
         subjects affected / exposed
    66 / 472 (13.98%)
    11 / 238 (4.62%)
         occurrences all number
    73
    15
    Oropharyngeal pain
         subjects affected / exposed
    74 / 472 (15.68%)
    31 / 238 (13.03%)
         occurrences all number
    103
    47
    Rhinorrhoea
         subjects affected / exposed
    43 / 472 (9.11%)
    18 / 238 (7.56%)
         occurrences all number
    52
    19
    Productive cough
         subjects affected / exposed
    25 / 472 (5.30%)
    14 / 238 (5.88%)
         occurrences all number
    31
    16
    Psychiatric disorders
    Depression
         subjects affected / exposed
    23 / 472 (4.87%)
    12 / 238 (5.04%)
         occurrences all number
    24
    12
    Anxiety
         subjects affected / exposed
    31 / 472 (6.57%)
    12 / 238 (5.04%)
         occurrences all number
    33
    12
    Insomnia
         subjects affected / exposed
    78 / 472 (16.53%)
    39 / 238 (16.39%)
         occurrences all number
    104
    49
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    95 / 472 (20.13%)
    45 / 238 (18.91%)
         occurrences all number
    195
    107
    Aspartate aminotransferase increased
         subjects affected / exposed
    72 / 472 (15.25%)
    29 / 238 (12.18%)
         occurrences all number
    141
    41
    Ejection fraction decreased
         subjects affected / exposed
    35 / 472 (7.42%)
    15 / 238 (6.30%)
         occurrences all number
    43
    15
    Haemoglobin decreased
         subjects affected / exposed
    41 / 472 (8.69%)
    8 / 238 (3.36%)
         occurrences all number
    85
    11
    Neutrophil count decreased
         subjects affected / exposed
    44 / 472 (9.32%)
    23 / 238 (9.66%)
         occurrences all number
    124
    48
    Weight increased
         subjects affected / exposed
    19 / 472 (4.03%)
    26 / 238 (10.92%)
         occurrences all number
    26
    29
    Weight decreased
         subjects affected / exposed
    99 / 472 (20.97%)
    13 / 238 (5.46%)
         occurrences all number
    111
    14
    White blood cell count decreased
         subjects affected / exposed
    34 / 472 (7.20%)
    14 / 238 (5.88%)
         occurrences all number
    103
    34
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    32 / 472 (6.78%)
    10 / 238 (4.20%)
         occurrences all number
    36
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    74 / 472 (15.68%)
    37 / 238 (15.55%)
         occurrences all number
    120
    85
    Headache
         subjects affected / exposed
    130 / 472 (27.54%)
    70 / 238 (29.41%)
         occurrences all number
    311
    149
    Dysgeusia
         subjects affected / exposed
    59 / 472 (12.50%)
    24 / 238 (10.08%)
         occurrences all number
    78
    28
    Hypoaesthesia
         subjects affected / exposed
    61 / 472 (12.92%)
    36 / 238 (15.13%)
         occurrences all number
    94
    53
    Neuropathy peripheral
         subjects affected / exposed
    136 / 472 (28.81%)
    58 / 238 (24.37%)
         occurrences all number
    211
    78
    Neurotoxicity
         subjects affected / exposed
    40 / 472 (8.47%)
    24 / 238 (10.08%)
         occurrences all number
    49
    37
    Paraesthesia
         subjects affected / exposed
    35 / 472 (7.42%)
    25 / 238 (10.50%)
         occurrences all number
    46
    37
    Peripheral sensory neuropathy
         subjects affected / exposed
    61 / 472 (12.92%)
    37 / 238 (15.55%)
         occurrences all number
    82
    42
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    143 / 472 (30.30%)
    38 / 238 (15.97%)
         occurrences all number
    231
    77
    Leukopenia
         subjects affected / exposed
    71 / 472 (15.04%)
    24 / 238 (10.08%)
         occurrences all number
    404
    128
    Neutropenia
         subjects affected / exposed
    177 / 472 (37.50%)
    59 / 238 (24.79%)
         occurrences all number
    540
    248
    Thrombocytopenia
         subjects affected / exposed
    46 / 472 (9.75%)
    6 / 238 (2.52%)
         occurrences all number
    65
    7
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    55 / 472 (11.65%)
    26 / 238 (10.92%)
         occurrences all number
    77
    51
    Abdominal pain
         subjects affected / exposed
    71 / 472 (15.04%)
    29 / 238 (12.18%)
         occurrences all number
    116
    40
    Aphthous ulcer
         subjects affected / exposed
    25 / 472 (5.30%)
    4 / 238 (1.68%)
         occurrences all number
    38
    9
    Constipation
         subjects affected / exposed
    101 / 472 (21.40%)
    51 / 238 (21.43%)
         occurrences all number
    179
    81
    Diarrhoea
         subjects affected / exposed
    267 / 472 (56.57%)
    112 / 238 (47.06%)
         occurrences all number
    760
    300
    Dyspepsia
         subjects affected / exposed
    50 / 472 (10.59%)
    26 / 238 (10.92%)
         occurrences all number
    74
    44
    Mouth ulceration
         subjects affected / exposed
    60 / 472 (12.71%)
    14 / 238 (5.88%)
         occurrences all number
    160
    36
    Haemorrhoids
         subjects affected / exposed
    32 / 472 (6.78%)
    7 / 238 (2.94%)
         occurrences all number
    34
    7
    Stomatitis
         subjects affected / exposed
    315 / 472 (66.74%)
    77 / 238 (32.35%)
         occurrences all number
    898
    148
    Nausea
         subjects affected / exposed
    154 / 472 (32.63%)
    83 / 238 (34.87%)
         occurrences all number
    297
    213
    Toothache
         subjects affected / exposed
    35 / 472 (7.42%)
    21 / 238 (8.82%)
         occurrences all number
    51
    34
    Vomiting
         subjects affected / exposed
    122 / 472 (25.85%)
    55 / 238 (23.11%)
         occurrences all number
    223
    111
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    29 / 472 (6.14%)
    4 / 238 (1.68%)
         occurrences all number
    60
    8
    Alopecia
         subjects affected / exposed
    221 / 472 (46.82%)
    125 / 238 (52.52%)
         occurrences all number
    240
    129
    Dry skin
         subjects affected / exposed
    37 / 472 (7.84%)
    20 / 238 (8.40%)
         occurrences all number
    42
    26
    Erythema
         subjects affected / exposed
    49 / 472 (10.38%)
    16 / 238 (6.72%)
         occurrences all number
    83
    24
    Nail disorder
         subjects affected / exposed
    68 / 472 (14.41%)
    27 / 238 (11.34%)
         occurrences all number
    84
    35
    Pruritus
         subjects affected / exposed
    64 / 472 (13.56%)
    24 / 238 (10.08%)
         occurrences all number
    103
    35
    Rash
         subjects affected / exposed
    191 / 472 (40.47%)
    49 / 238 (20.59%)
         occurrences all number
    394
    92
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    40 / 472 (8.47%)
    9 / 238 (3.78%)
         occurrences all number
    48
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    80 / 472 (16.95%)
    41 / 238 (17.23%)
         occurrences all number
    174
    60
    Back pain
         subjects affected / exposed
    72 / 472 (15.25%)
    42 / 238 (17.65%)
         occurrences all number
    97
    58
    Bone pain
         subjects affected / exposed
    30 / 472 (6.36%)
    14 / 238 (5.88%)
         occurrences all number
    39
    15
    Musculoskeletal pain
         subjects affected / exposed
    37 / 472 (7.84%)
    17 / 238 (7.14%)
         occurrences all number
    56
    19
    Muscle spasms
         subjects affected / exposed
    33 / 472 (6.99%)
    9 / 238 (3.78%)
         occurrences all number
    55
    11
    Myalgia
         subjects affected / exposed
    78 / 472 (16.53%)
    45 / 238 (18.91%)
         occurrences all number
    150
    102
    Pain in extremity
         subjects affected / exposed
    86 / 472 (18.22%)
    39 / 238 (16.39%)
         occurrences all number
    131
    53
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    28 / 472 (5.93%)
    8 / 238 (3.36%)
         occurrences all number
    37
    11
    Nasopharyngitis
         subjects affected / exposed
    90 / 472 (19.07%)
    47 / 238 (19.75%)
         occurrences all number
    214
    134
    Influenza
         subjects affected / exposed
    36 / 472 (7.63%)
    24 / 238 (10.08%)
         occurrences all number
    62
    36
    Paronychia
         subjects affected / exposed
    26 / 472 (5.51%)
    8 / 238 (3.36%)
         occurrences all number
    45
    8
    Pharyngitis
         subjects affected / exposed
    25 / 472 (5.30%)
    5 / 238 (2.10%)
         occurrences all number
    29
    5
    Pneumonia
         subjects affected / exposed
    33 / 472 (6.99%)
    10 / 238 (4.20%)
         occurrences all number
    37
    11
    Upper respiratory tract infection
         subjects affected / exposed
    67 / 472 (14.19%)
    34 / 238 (14.29%)
         occurrences all number
    128
    50
    Rhinitis
         subjects affected / exposed
    30 / 472 (6.36%)
    14 / 238 (5.88%)
         occurrences all number
    48
    19
    Urinary tract infection
         subjects affected / exposed
    56 / 472 (11.86%)
    17 / 238 (7.14%)
         occurrences all number
    107
    28
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    110 / 472 (23.31%)
    36 / 238 (15.13%)
         occurrences all number
    170
    69
    Hypercholesterolaemia
         subjects affected / exposed
    88 / 472 (18.64%)
    23 / 238 (9.66%)
         occurrences all number
    128
    31
    Hyperglycaemia
         subjects affected / exposed
    58 / 472 (12.29%)
    13 / 238 (5.46%)
         occurrences all number
    88
    27
    Hypertriglyceridaemia
         subjects affected / exposed
    68 / 472 (14.41%)
    17 / 238 (7.14%)
         occurrences all number
    130
    32
    Hypocalcaemia
         subjects affected / exposed
    24 / 472 (5.08%)
    4 / 238 (1.68%)
         occurrences all number
    34
    6
    Hypokalaemia
         subjects affected / exposed
    68 / 472 (14.41%)
    9 / 238 (3.78%)
         occurrences all number
    134
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2009
    In the original protocol, primary efficacy endpoint was based on independent central review of radiology data. In protocol amendment 1, the primary efficacy endpoint was changed to progression-free survival (PFS) assessed using local radiological assessment. The other changes introduced in amendment 1 were: Information on mTOR mechanism of action, safety & PK was updated based on the latest published data & updated everolimus Investigator Brochure Version 8. Management of hyperglycemia was updated as per the most recent everolimus Core Data Sheet Version 1.3, dated 22-Oct-2009. Guidance on the usage of CYP3A4 and/or P-glycoprotein (P-gp) inducers & inhibitors was modified to be consistent with Internal Clinical Pharmacology Drug-Drug interaction memo, which was updated 02-Dec-2009; Inclusion criterion #8 was updated with clarification that in the metastatic setting the discontinuation of endocrine therapy before randomization should be due to disease progression. Exclusion criteria #16 was updated with notes explaining 3rd space fluid accumulation. - Guidelines regarding the management of hepatitis B virus and hepatitis C virus infections were added; Modification of neutropenia dose adjustment guidelines, allowing reintroduction at the same dose level if improvement occurs within 7 days; Exploratory PK analyses was added to explore exposure-response relationships between selected efficacy end points/safety parameters/biomarkers & everolimus exposure (Cmin and C2h); Mandate for the IDMC to review PK data was removed. Therefore, ongoing PK data were not be submitted to the IDMC unless specifically requested; Everolimus was now to be administered after meals in clinical studies. This approach had been approved as the global strategy within the everolimus program to achieve consistency between clinical studies; Administrative and typographical revisions were made.
    31 Dec 2012
    This amendment, implemented prior to the planned interim analysis, replaced 514 with 420 events required for the final PFS analysis. It was noted that a higher percentage of patients than anticipated discontinued the study prior to a PFS event & it was highly unlikely that originally targeted events required to perform the final analysis would be observed. Based on number & timing of deaths observed, it was projected that the 434 OS events would not be reached prior to end of 2016. Due to longer time interval between the interim/final PFS analysis & final OS analysis, an additional OS interim analysis was added, to be performed after observing approximately 329 (75% information fraction) deaths. As a result of adding an additional OS interim analysis & to maintain the 80% power to detect HR of 0.75 as was originally planned, final number of OS events was revised to 438 from 434. Protocol Synopsis, primary & key secondary efficacy analysis section including sample size & statistical power sections were revised. List of pre-specified subgroups assessing consistency of the efficacy results was updated based on emerging data in the treatment of HER2 positive breast cancer patients & also efficacy of everolimus in ER+ patients based on another study data. Additional safety updates: re-definition of hepatitis C reactivation & AST/ALT dose adjustment guidelines were updated to be consistent with current safety recommendations with everolimus use; language emphasizing the risk of infection specifically pulmonary infection & sepsis; language outlining reproductive toxicity & use of everolimus with guidelines for contraceptive use & pregnancy follow-up; a clarification was added to confirm SAE data was to be collected in the safety database, not clinical database for screen failure patients who signed the ICF. Other administrative changes were added, including updates on SSC membership, TRIO & Novartis Project Teams, change of CIRG’s name to TRIO & editorial clarifications.
    26 Mar 2014
    The primary purpose of this amendment was to add a second primary objective to evaluate PFS in the HR-negative subpopulation in addition to the full study population. Similarly OS and all other secondary objectives would be evaluated in HR-negative subpopulation in addition to the full study population. This amendment was supported by emerging pre-clinical and emerging scientific data from randomized Phase III studies of everolimus; and recent data from clinical studies using novel HER2 targeted therapies. The multiplicity arising from two tests performed to address two primary objectives was controlled via use of a weighted Hochberg procedure. Additional changes were: The protocol was updated with recent available clinical data from everolimus studies; data on HER2 targeted therapies in HR negative patients; and the number of patients with various malignancies exposed to everolimus; Sample size and statistical power; statistical hypothesis, model, and method of analysis; interim analysis for PFS and OS; and recording and processing of data were updated to address implications for the HR-negative subpopulation; Sections on schedule of assessments and disease-related events/outcomes were updated for consistency. Safety assessments were updated to clarify routine monitoring of vital signs; Administrative and typographical revisions were made.

    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.
    Of the 480 patients enrolled in the Everolimus arm, 8 were untreated and in the Placebo arm, of the 239 patients enrolled, 1 was untreated.
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