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    Clinical Trial Results:
    A three-arm, randomized, open label, phase II study of everolimus in combination with exemestane versus everolimus alone versus capecitabine in the treatment of postmenopausal women with estrogen receptor positive, locally advanced, recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole or anastrozole

    Summary
    EudraCT number
    		 2012-003757-28
    Trial protocol
    		 BE   SE   GB   IE   DK   ES   HU  
    Global end of trial date
    30 Jul 2018

    Results information
    Results version number
    		 v3(current)
    This version publication date
    20 Mar 2021
    First version publication date
    02 Jun 2019
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001Y2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01783444
    WHO universal trial number (UTN)
    		 -
    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
    30 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to estimate the hazard ratio (HR) of progression free survival (PFS) for everolimus plus exemestane versus everolimus alone in postmenopausal women with ER-positive, HER2-negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.
    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
    26 Feb 2016
    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: 16
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    India: 10
    Country: Number of subjects enrolled
    Ireland: 9
    Country: Number of subjects enrolled
    Lebanon: 18
    Country: Number of subjects enrolled
    Malaysia: 11
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 16
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    309
    EEA total number of subjects
    91
    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)
    198
    From 65 to 84 years
    109
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 84 centers in 18 countries worldwide: Belgium (1), Denmark (6), Hungary (3), Ireland (3), Spain (4), Sweden (6), United Kingdom (3), United States (19), Argentina (6), Brazil (5), Peru (4), India (4), Lebanon (5), Malaysia (2), Russia (3), Thailand (3), Turkey (3) Australia (4)

    Pre-assignment
    Screening details
    		 A total of 300 subjects were planned and total of 309 subjects were randomized to everolimus plus exemestane (control arm) (N = 104), everolimus alone (N = 103), or capecitabine (N = 102).

    Period 1
    Period 1 title
    Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Everolimus 10 mg + Exemestane 25 mg
    Arm description
    		 Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane, tablets for oral use, 25 mg per day in (locally supplied)

    Arm title
    		 Everolimus 10 mg
    Arm description
    		 Everolimus (10 mg daily) (investigational arm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

    Arm title
    		 Capecitabine 1250 mg/m2
    Arm description
    		 Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied)

    Number of subjects in period 1
    		Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Started
    104
    103
    102
    Safety Set
    104
    103
    102
    Completed
    0
    0
    0
    Not completed
    104
    103
    102
         Adverse event, serious fatal
    2
    2
    2
         Consent withdrawn by subject
    6
    8
    9
         Physician decision
    8
    6
    5
         Adverse event, non-fatal
    9
    20
    19
         Administrative problems
    2
    -
    1
         Disease Progression
    76
    66
    64
         Protocol deviation
    1
    1
    2
    Period 2
    Period 2 title
    Post-Treatment Efficacy Follow-Up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Everolimus 10 mg + Exemestane 25 mg
    Arm description
    		 Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane, tablets for oral use, 25 mg per day in (locally supplied)

    Arm title
    		 Everolimus 10 mg
    Arm description
    		 Everolimus (10 mg daily) (investigational arm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

    Arm title
    		 Capecitabine 1250 mg/m2
    Arm description
    		 Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied)

    Number of subjects in period 2
    		Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Started
    96
    93
    91
    Completed
    0
    0
    0
    Not completed
    96
    93
    91
         Adverse event, serious fatal
    9
    7
    5
         Consent withdrawn by subject
    4
    8
    8
         Followup phase completed as per protocol
    69
    53
    52
         New cancer therapy
    7
    16
    15
         Administrative problems
    -
    1
    -
         Disease Progression
    7
    8
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus 10 mg + Exemestane 25 mg
    Reporting group description
    		 Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).

    Reporting group title
    Everolimus 10 mg
    Reporting group description
    		 Everolimus (10 mg daily) (investigational arm).

    Reporting group title
    Capecitabine 1250 mg/m2
    Reporting group description
    		 Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).

    Reporting group values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2 Total
    Number of subjects
    		 104 103 102 309
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 65 64 69 198
        From 65-84 years
    		 38 38 33 109
        85 years and over
    		 1 1 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.9 ( 10.47 ) 61.3 ( 9.08 ) 59.7 ( 10.50 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 104 103 102 309
        Male
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 78 85 91 254
        Black
    		 1 2 0 3
        Asian
    		 11 8 8 27
        Native American
    		 3 2 0 5
        Other
    		 11 6 3 20
    ECOG Performance Status
    Units: Subjects
        No Restrictions
    		 54 48 57 159
        Only Light Work
    		 42 50 39 131
        Only Self Care
    		 5 3 4 12
        Missing
    		 3 2 2 7

    End points

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    End points reporting groups
    Reporting group title
    Everolimus 10 mg + Exemestane 25 mg
    Reporting group description
    		 Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).

    Reporting group title
    Everolimus 10 mg
    Reporting group description
    		 Everolimus (10 mg daily) (investigational arm).

    Reporting group title
    Capecitabine 1250 mg/m2
    Reporting group description
    		 Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
    Reporting group title
    Everolimus 10 mg + Exemestane 25 mg
    Reporting group description
    		 Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).

    Reporting group title
    Everolimus 10 mg
    Reporting group description
    		 Everolimus (10 mg daily) (investigational arm).

    Reporting group title
    Capecitabine 1250 mg/m2
    Reporting group description
    		 Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).

    Primary: Progression Free Survival (PFS) - Everolimus plus exemestane versus everolimus alone

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    End point title
    		 Progression Free Survival (PFS) - Everolimus plus exemestane versus everolimus alone [1]
    End point description
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.
    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 39 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary endpoint "Progression Free Survival (PFS) - Everolimus plus exemestane versus everolimus alone" only apply to Treatment Arms: "Everolimus 10 mg + Exemestane 25 mg" and "Everolimus 10 mg"
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg
    Number of subjects analysed
    104
    103
    Units: Months
        median (confidence interval 90%)
    8.41 (6.60 to 9.72)
    6.77 (5.52 to 7.20)
    Statistical analysis title
    		 PFS - Everolimus+exemestane vs everolimus alone
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.97
    Notes
    [2] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)

    Secondary: Progression Free Survival (PFS) - Everolimus plus exemestane versus Capecitabine alone

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    End point title
    		 Progression Free Survival (PFS) - Everolimus plus exemestane versus Capecitabine alone [3]
    End point description
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.
    End point type
    Secondary
    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 39 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Primary endpoint "Progression Free Survival (PFS) - Everolimus plus exemestane versus Capecitabine alone" only apply to Treatment Arms: "Everolimus 10 mg + Exemestane 25 mg" and "Capecitabine 1250 mg/m2"
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    102
    Units: Months
        median (confidence interval 90%)
    8.41 (6.60 to 9.72)
    9.59 (8.25 to 15.05)
    Statistical analysis title
    		 PFS - Everolimus+exemestane vs Capecitabine alone
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.66
    Notes
    [4] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.
    End point type
    Secondary
    End point timeframe
    Every 3 months following end of treatment visit, assessed for approximately 54 months
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Months
        median (confidence interval 90%)
    23.06 (19.48 to 27.96)
    29.27 (24.28 to 31.77)
    25.56 (23.82 to 33.35)
    Statistical analysis title
    		 OS - Everolimus+Exemestane vs Everolimus
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.7
    Notes
    [5] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
    Statistical analysis title
    		 OS - Everolimus+Exemestane vs Capecitabine
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.79
    Notes
    [6] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    Overall Response Rate (ORR) as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1 This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at baseline are absent at subsequent visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Only descriptive statistics.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Percentage of Participants
        number (confidence interval 90%)
    21 (13.9 to 27.8)
    12 (6.9 to 18.2)
    23 (15.9 to 30.4)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator’s assessment according to RECIST 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, Stable disease (SD), neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; CBR = CR+PR+SD. Only descriptive statistics.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Percentage of Participants
        number (confidence interval 90%)
    59 (48.2 to 65.0)
    43 (33.5 to 50.3)
    53 (43.4 to 60.5)
    No statistical analyses for this end point

    Secondary: Time to 10% definitive deterioration in the global health status / Quality of life

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    End point title
    		 Time to 10% definitive deterioration in the global health status / Quality of life
    End point description
    The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive 10% (5-point) deterioration is defined as a decrease in score by at least 10% (5-points) compared to baseline, with no later increase above this threshold observed during the course of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks up to about 43 months
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Weeks
        median (confidence interval 90%)
    30.86 (24.29 to 78.00)
    23.86 (12.57 to 24.71)
    61.29 (36.86 to 143.71)
    Statistical analysis title
    		 QLQ-C30 Everolimus+Exemestane vs Everolimus
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.88
    Notes
    [7] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
    Statistical analysis title
    		 QLQ-C30 Everolimus+Exemestane vs Capecitabine
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.91
    Notes
    [8] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)

    Secondary: Time to Eastern Cooperative Oncology Group (ECOG) performance deterioration

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    End point title
    		 Time to Eastern Cooperative Oncology Group (ECOG) performance deterioration
    End point description
    The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess physical health of subjects,ranging from 0 (most active) to 5 (least active). Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks up to about 43 months
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Weeks
        median (confidence interval 90%)
    72.57 (38.71 to 999)
    126.57 (72.14 to 999)
    120.00 (72.57 to 999)
    Statistical analysis title
    		 ECOG - Everolimus+Exemestane vs Capecitabine
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.77
    Notes
    [9] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)
    Statistical analysis title
    		 ECOG - Everolimus+Exemestane vs Everolimus
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.66
    Notes
    [10] - Hazard ratio obtained from stratified Cox model (stratified by presence/absence of visceral metastasis as per IWRS)

    Secondary: Mean change in Treatment Satisfaction Questionnaire for Medication (TSQM) between week 3 and 12

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    End point title
    		 Mean change in Treatment Satisfaction Questionnaire for Medication (TSQM) between week 3 and 12
    End point description
    TSQM was used to measure the Patients’ self-reported satisfaction or dissatisfaction with the study treatment. The differences in mean scale scores between weeks 3 and 12 comparing treatment satisfaction in the different treatment arms: everolimus + exemestane combination therapy versus everolimus monotherapy, and everolimus + exemestane combination therapy versus capecitabine monotherapy. The TSQM version 1.4 domain scores range from 0 to 100 with higher scores representing a higher satisfaction on that domain.
    End point type
    Secondary
    End point timeframe
    Week 3, Week 12
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Side-effects
    -4.8 ( 28.88 )
    -9.1 ( 21.88 )
    -2.6 ( 22.45 )
        Effectiveness
    -2.2 ( 20.15 )
    1.2 ( 26.51 )
    1.2 ( 21.61 )
        Convenience
    -0.6 ( 12.00 )
    1.0 ( 16.41 )
    0.5 ( 17.67 )
        Global satisfaction
    -1.0 ( 17.32 )
    1.8 ( 20.80 )
    2.3 ( 16.96 )
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Everolimus
    Statistical analysis description
    Side-effects
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 11.9
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Capecitabine
    Statistical analysis description
    Side-effects
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.9
         upper limit
    		 5.5
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Everolimus
    Statistical analysis description
    Effectiveness
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -10.4
         upper limit
    		 3.8
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Capecitabine
    Statistical analysis description
    Effectiveness
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 3
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Everolimus
    Statistical analysis description
    Convenience
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 2.5
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Capecitabine
    Statistical analysis description
    Convenience
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 3.3
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Everolimus
    Statistical analysis description
    Global Satisfaction
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Everolimus 10 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 2.9
    Statistical analysis title
    		 TSQM - Everolimus+Exemestane vs Capecitabine
    Statistical analysis description
    Global Satisfaction
    Comparison groups
    Everolimus 10 mg + Exemestane 25 mg v Capecitabine 1250 mg/m2
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 1.9

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 224 weeks (treatment duration ranged from 1.3 to 220.0 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 5 years. Patients who didn’t die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
    End point type
    Post-hoc
    End point timeframe
    up to 224 weeks (on-treatment), up to approximately 5 years (study duration)
    End point values
    		 Everolimus 10 mg + Exemestane 25 mg Everolimus 10 mg Capecitabine 1250 mg/m2
    Number of subjects analysed
    104
    103
    102
    Units: Participants
        On-treatment deaths
    9
    5
    2
        Post-treatment deaths
    62
    55
    57
        All deaths
    71
    60
    59
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Everolimus 10mg +@Exemestane 25mg
    Reporting group description
    		 Everolimus 10mg +@Exemestane 25mg

    Reporting group title
    Everolimus 10mg
    Reporting group description
    		 Everolimus 10mg

    Reporting group title
    Capecitabine@1250mg/m2
    Reporting group description
    		 Capecitabine@1250mg/m2

    Serious adverse events
    		 Everolimus 10mg +@Exemestane 25mg Everolimus 10mg Capecitabine@1250mg/m2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 104 (35.58%)
    30 / 103 (29.13%)
    30 / 102 (29.41%)
         number of deaths (all causes)
    9
    5
    2
         number of deaths resulting from adverse events
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 103 (1.94%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    4 / 102 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 104 (3.85%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 104 (1.92%)
    2 / 103 (1.94%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 103 (0.97%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 104 (1.92%)
    3 / 103 (2.91%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 103 (0.97%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 104 (0.96%)
    3 / 103 (2.91%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 104 (0.96%)
    3 / 103 (2.91%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 103 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 103 (1.94%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 104 (2.88%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 103 (1.94%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 103 (0.97%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin toxicity
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 104 (2.88%)
    4 / 103 (3.88%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 104 (7.69%)
    4 / 103 (3.88%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    3 / 104 (2.88%)
    1 / 103 (0.97%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 103 (0.97%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 103 (0.97%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus 10mg +@Exemestane 25mg Everolimus 10mg Capecitabine@1250mg/m2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 104 (99.04%)
    100 / 103 (97.09%)
    99 / 102 (97.06%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 104 (14.42%)
    8 / 103 (7.77%)
    5 / 102 (4.90%)
         occurrences all number
    17
    9
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    25 / 104 (24.04%)
    9 / 103 (8.74%)
    24 / 102 (23.53%)
         occurrences all number
    29
    10
    34
    Fatigue
         subjects affected / exposed
    39 / 104 (37.50%)
    32 / 103 (31.07%)
    34 / 102 (33.33%)
         occurrences all number
    55
    36
    50
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 104 (5.77%)
    4 / 103 (3.88%)
    5 / 102 (4.90%)
         occurrences all number
    6
    6
    6
    Oedema peripheral
         subjects affected / exposed
    30 / 104 (28.85%)
    22 / 103 (21.36%)
    16 / 102 (15.69%)
         occurrences all number
    35
    27
    22
    Pyrexia
         subjects affected / exposed
    18 / 104 (17.31%)
    12 / 103 (11.65%)
    9 / 102 (8.82%)
         occurrences all number
    38
    14
    10
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    6 / 104 (5.77%)
    1 / 103 (0.97%)
    6 / 102 (5.88%)
         occurrences all number
    7
    1
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    37 / 104 (35.58%)
    16 / 103 (15.53%)
    18 / 102 (17.65%)
         occurrences all number
    47
    20
    40
    Dyspnoea
         subjects affected / exposed
    18 / 104 (17.31%)
    19 / 103 (18.45%)
    17 / 102 (16.67%)
         occurrences all number
    21
    20
    19
    Epistaxis
         subjects affected / exposed
    13 / 104 (12.50%)
    11 / 103 (10.68%)
    0 / 102 (0.00%)
         occurrences all number
    13
    13
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 104 (3.85%)
    7 / 103 (6.80%)
    1 / 102 (0.98%)
         occurrences all number
    4
    8
    1
    Pleural effusion
         subjects affected / exposed
    4 / 104 (3.85%)
    5 / 103 (4.85%)
    6 / 102 (5.88%)
         occurrences all number
    4
    6
    6
    Pneumonitis
         subjects affected / exposed
    22 / 104 (21.15%)
    21 / 103 (20.39%)
    0 / 102 (0.00%)
         occurrences all number
    27
    26
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 104 (5.77%)
    2 / 103 (1.94%)
    5 / 102 (4.90%)
         occurrences all number
    6
    2
    6
    Depression
         subjects affected / exposed
    8 / 104 (7.69%)
    5 / 103 (4.85%)
    5 / 102 (4.90%)
         occurrences all number
    9
    5
    5
    Insomnia
         subjects affected / exposed
    10 / 104 (9.62%)
    8 / 103 (7.77%)
    11 / 102 (10.78%)
         occurrences all number
    10
    8
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 104 (15.38%)
    10 / 103 (9.71%)
    6 / 102 (5.88%)
         occurrences all number
    19
    12
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 104 (15.38%)
    14 / 103 (13.59%)
    9 / 102 (8.82%)
         occurrences all number
    21
    14
    9
    Blood cholesterol increased
         subjects affected / exposed
    6 / 104 (5.77%)
    9 / 103 (8.74%)
    1 / 102 (0.98%)
         occurrences all number
    10
    12
    2
    Blood creatinine increased
         subjects affected / exposed
    8 / 104 (7.69%)
    6 / 103 (5.83%)
    4 / 102 (3.92%)
         occurrences all number
    11
    7
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    15 / 104 (14.42%)
    16 / 103 (15.53%)
    2 / 102 (1.96%)
         occurrences all number
    18
    18
    2
    Platelet count decreased
         subjects affected / exposed
    8 / 104 (7.69%)
    1 / 103 (0.97%)
    1 / 102 (0.98%)
         occurrences all number
    8
    2
    1
    Weight decreased
         subjects affected / exposed
    31 / 104 (29.81%)
    25 / 103 (24.27%)
    15 / 102 (14.71%)
         occurrences all number
    36
    27
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 104 (7.69%)
    9 / 103 (8.74%)
    6 / 102 (5.88%)
         occurrences all number
    8
    9
    6
    Dysgeusia
         subjects affected / exposed
    17 / 104 (16.35%)
    20 / 103 (19.42%)
    14 / 102 (13.73%)
         occurrences all number
    19
    20
    18
    Headache
         subjects affected / exposed
    17 / 104 (16.35%)
    16 / 103 (15.53%)
    13 / 102 (12.75%)
         occurrences all number
    19
    17
    18
    Neuropathy peripheral
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 103 (0.97%)
    7 / 102 (6.86%)
         occurrences all number
    1
    1
    7
    Paraesthesia
         subjects affected / exposed
    6 / 104 (5.77%)
    2 / 103 (1.94%)
    3 / 102 (2.94%)
         occurrences all number
    6
    3
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    32 / 104 (30.77%)
    26 / 103 (25.24%)
    22 / 102 (21.57%)
         occurrences all number
    41
    29
    25
    Neutropenia
         subjects affected / exposed
    4 / 104 (3.85%)
    4 / 103 (3.88%)
    14 / 102 (13.73%)
         occurrences all number
    4
    4
    15
    Thrombocytopenia
         subjects affected / exposed
    4 / 104 (3.85%)
    7 / 103 (6.80%)
    3 / 102 (2.94%)
         occurrences all number
    5
    9
    3
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 104 (1.92%)
    1 / 103 (0.97%)
    7 / 102 (6.86%)
         occurrences all number
    2
    2
    8
    Lacrimation increased
         subjects affected / exposed
    3 / 104 (2.88%)
    4 / 103 (3.88%)
    9 / 102 (8.82%)
         occurrences all number
    3
    4
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 104 (9.62%)
    9 / 103 (8.74%)
    13 / 102 (12.75%)
         occurrences all number
    12
    9
    19
    Abdominal pain upper
         subjects affected / exposed
    6 / 104 (5.77%)
    3 / 103 (2.91%)
    6 / 102 (5.88%)
         occurrences all number
    6
    3
    12
    Constipation
         subjects affected / exposed
    14 / 104 (13.46%)
    15 / 103 (14.56%)
    18 / 102 (17.65%)
         occurrences all number
    16
    15
    23
    Diarrhoea
         subjects affected / exposed
    36 / 104 (34.62%)
    34 / 103 (33.01%)
    55 / 102 (53.92%)
         occurrences all number
    61
    46
    104
    Dry mouth
         subjects affected / exposed
    10 / 104 (9.62%)
    11 / 103 (10.68%)
    12 / 102 (11.76%)
         occurrences all number
    13
    11
    14
    Dyspepsia
         subjects affected / exposed
    8 / 104 (7.69%)
    5 / 103 (4.85%)
    7 / 102 (6.86%)
         occurrences all number
    10
    5
    10
    Mouth ulceration
         subjects affected / exposed
    15 / 104 (14.42%)
    13 / 103 (12.62%)
    1 / 102 (0.98%)
         occurrences all number
    21
    17
    3
    Nausea
         subjects affected / exposed
    35 / 104 (33.65%)
    21 / 103 (20.39%)
    52 / 102 (50.98%)
         occurrences all number
    51
    24
    79
    Stomatitis
         subjects affected / exposed
    51 / 104 (49.04%)
    45 / 103 (43.69%)
    24 / 102 (23.53%)
         occurrences all number
    87
    61
    30
    Toothache
         subjects affected / exposed
    5 / 104 (4.81%)
    6 / 103 (5.83%)
    1 / 102 (0.98%)
         occurrences all number
    6
    12
    1
    Vomiting
         subjects affected / exposed
    20 / 104 (19.23%)
    14 / 103 (13.59%)
    29 / 102 (28.43%)
         occurrences all number
    33
    18
    38
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 104 (5.77%)
    3 / 103 (2.91%)
    6 / 102 (5.88%)
         occurrences all number
    6
    3
    8
    Dermatitis acneiform
         subjects affected / exposed
    7 / 104 (6.73%)
    4 / 103 (3.88%)
    0 / 102 (0.00%)
         occurrences all number
    11
    4
    0
    Dry skin
         subjects affected / exposed
    11 / 104 (10.58%)
    6 / 103 (5.83%)
    14 / 102 (13.73%)
         occurrences all number
    12
    6
    15
    Erythema
         subjects affected / exposed
    6 / 104 (5.77%)
    4 / 103 (3.88%)
    3 / 102 (2.94%)
         occurrences all number
    7
    7
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 104 (2.88%)
    3 / 103 (2.91%)
    62 / 102 (60.78%)
         occurrences all number
    3
    5
    96
    Pruritus
         subjects affected / exposed
    11 / 104 (10.58%)
    8 / 103 (7.77%)
    7 / 102 (6.86%)
         occurrences all number
    13
    8
    10
    Rash
         subjects affected / exposed
    22 / 104 (21.15%)
    23 / 103 (22.33%)
    12 / 102 (11.76%)
         occurrences all number
    30
    32
    15
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    1
    0
    6
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    6 / 104 (5.77%)
    1 / 103 (0.97%)
    3 / 102 (2.94%)
         occurrences all number
    6
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 104 (10.58%)
    16 / 103 (15.53%)
    13 / 102 (12.75%)
         occurrences all number
    12
    22
    15
    Back pain
         subjects affected / exposed
    20 / 104 (19.23%)
    8 / 103 (7.77%)
    12 / 102 (11.76%)
         occurrences all number
    21
    9
    15
    Bone pain
         subjects affected / exposed
    9 / 104 (8.65%)
    4 / 103 (3.88%)
    7 / 102 (6.86%)
         occurrences all number
    13
    4
    9
    Muscle spasms
         subjects affected / exposed
    3 / 104 (2.88%)
    6 / 103 (5.83%)
    0 / 102 (0.00%)
         occurrences all number
    4
    6
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    10 / 104 (9.62%)
    7 / 103 (6.80%)
    8 / 102 (7.84%)
         occurrences all number
    13
    10
    9
    Musculoskeletal pain
         subjects affected / exposed
    11 / 104 (10.58%)
    5 / 103 (4.85%)
    9 / 102 (8.82%)
         occurrences all number
    11
    5
    10
    Myalgia
         subjects affected / exposed
    6 / 104 (5.77%)
    4 / 103 (3.88%)
    3 / 102 (2.94%)
         occurrences all number
    6
    4
    3
    Neck pain
         subjects affected / exposed
    6 / 104 (5.77%)
    1 / 103 (0.97%)
    4 / 102 (3.92%)
         occurrences all number
    6
    1
    4
    Pain in extremity
         subjects affected / exposed
    14 / 104 (13.46%)
    13 / 103 (12.62%)
    16 / 102 (15.69%)
         occurrences all number
    14
    15
    22
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 104 (5.77%)
    7 / 103 (6.80%)
    2 / 102 (1.96%)
         occurrences all number
    6
    12
    2
    Rash pustular
         subjects affected / exposed
    6 / 104 (5.77%)
    0 / 103 (0.00%)
    0 / 102 (0.00%)
         occurrences all number
    7
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 104 (7.69%)
    8 / 103 (7.77%)
    5 / 102 (4.90%)
         occurrences all number
    9
    11
    5
    Urinary tract infection
         subjects affected / exposed
    12 / 104 (11.54%)
    8 / 103 (7.77%)
    5 / 102 (4.90%)
         occurrences all number
    16
    11
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    35 / 104 (33.65%)
    32 / 103 (31.07%)
    27 / 102 (26.47%)
         occurrences all number
    42
    35
    34
    Dehydration
         subjects affected / exposed
    9 / 104 (8.65%)
    5 / 103 (4.85%)
    5 / 102 (4.90%)
         occurrences all number
    10
    6
    6
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 104 (2.88%)
    9 / 103 (8.74%)
    3 / 102 (2.94%)
         occurrences all number
    3
    9
    3
    Hyperglycaemia
         subjects affected / exposed
    13 / 104 (12.50%)
    18 / 103 (17.48%)
    8 / 102 (7.84%)
         occurrences all number
    20
    25
    8
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 104 (4.81%)
    15 / 103 (14.56%)
    9 / 102 (8.82%)
         occurrences all number
    8
    17
    9
    Hypokalaemia
         subjects affected / exposed
    11 / 104 (10.58%)
    6 / 103 (5.83%)
    5 / 102 (4.90%)
         occurrences all number
    14
    8
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2013
    Amendment 1 was issued when four subjects were randomized, six subjects were in screening and one subject was discontinued due to disease progression. The main purpose of amendment 1 was to introduce the following changes: 1) A new exclusion criterion was added to exclude subjects who were being treated with sorivudine or its chemically related analogues (e.g. brivudine) or it was required to have at least 4 weeks period between end of treatment with such drugs and randomization date. 2) To be consistent with exclusion criterion 20 (re-numbered as 18 after amendment), which excluded subjects under coumarin-derivate anticoagulants, the exclusion criterion 15 was updated to also exclude subjects under low dose warfarin treatment. 3) Besides the pre-specified final OS analysis, it was desirable to assess the treatment effect on overall survival at the time of the pre-specified final PFS analysis. So this interim OS analysis was added in the amendment. No multiple testing considerations were needed because hypothesis testing was not part of either OS analysis.
    16 Jun 2014
    Amendment 2 was issued when 119 subjects were randomized. The main purpose of amendment 2 was to introduce the following change: • An interim analysis was added to allow early termination of the everolimus monotherapy arm when approximately 75 PFS events had been observed as per local tumor assessment, across the two arms: everolimus monotherapy and everolimus + exemestane combination arm. The intent of adding this interim analysis was to allow for the potential of early termination of the everolimus monotherapy arm, in case the efficacy in the everolimus monotherapy arm was far inferior to the everolimus + exemestane combination arm. This approach was endorsed by the Data Monitoring Committee (DMC) and Study Steering Committee.
    18 Apr 2017
    Amendment 3 was issued when study was fully recruited with 309 subjects, with the last subject randomized on 24-Nov-2014. Per initial protocol, the final PFS analysis was to be performed when at least 150 PFS events have been documented in 1) everolimus plus exemestane arm, and everolimus monotherapy arm, and 2) the everolimus plus exemestane arm, and capecitabine monotherapy arm. The OS analyses were to be conducted with two data cut-off dates; 2 years after the last subject’s randomization and at the time of the final PFS analysis. Based on the observed 146 PFS events, there were 4 events less in one of the comparison, and there was a high risk of not reaching the events over extended time due to long lasting stable disease status in the remaining subjects. From the statistical perspective, loss of precision in the HR estimate with ≤ 4 events short of required 150 was considered minimal. In order to meet the regulatory commitment for submitting the CSR without affecting the scientific objective of the study, it was proposed in the protocol amendment 3 to: 1) Perform the final PFS analysis after approximately (instead of at least) 150 PFS events have been documented for each comparison. 2) Perform the final OS analysis at the same time as the final PFS analysis using the same data cut-off date. This amendment was considered “non-substantial” as it did not affect the subject management or the statistical analyses of the study.

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

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