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    Clinical Trial Results:
    A phase III randomized, double blind placebo controlled study of BKM120 with fulvestrant, in postmenopausal women with hormone receptor-positive HER2-negative locally advanced or metastatic breast cancer which progressed on or after aromatase inhibitor treatment

    Summary
    EudraCT number
    		 2011-005524-17
    Trial protocol
    		 GB   BE   DE   AT   NL   IT   HU   FR   GR   CZ   SK  
    Global end of trial date
    19 Apr 2019

    Results information
    Results version number
    		 v1
    This version publication date
    01 May 2020
    First version publication date
    01 May 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CBKM120F2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01610284
    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
    19 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The co-primary objective was: To determine whether treatment with BKM120 plus fulvestrant prolongs PFS based on local investigator assessment compared to treatment with placebo plus fulvestrant for all patients in the Main Study Cohort (known PI3K pathway activation status). and/or To determine whether treatment with BKM120 plus fulvestrant prolongs PFS based on local investigator assessment compared to treatment with placebo plus fulvestrant for all patients (Full Population) or To determine whether treatment with BKM120 plus fulvestrant prolongs PFS based on local investigator assessment compared to treatment with placebo plus fulvestrant for PI3K pathway activated sub-population.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2012
    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: 18
    Country: Number of subjects enrolled
    Australia: 39
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 46
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 119
    Country: Number of subjects enrolled
    China: 47
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    France: 96
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Israel: 32
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    Japan: 103
    Country: Number of subjects enrolled
    Korea, Republic of: 55
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Singapore: 10
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Spain: 103
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Taiwan: 33
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    United States: 156
    Worldwide total number of subjects
    1147
    EEA total number of subjects
    458
    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)
    707
    From 65 to 84 years
    432
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 274 centers in 29 countries worldwide (Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, Japan, Republic of Korea, The Netherlands, Peru, Poland, Russia, Singapore, Slovakia, South Africa, Spain, Switzerland, Taiwan, Thailand, UK and USA.).

    Pre-assignment
    Screening details
    		 Approximately 1200 patients were planned to be enrolled in the study. A total of 1147 patients were randomized and analyzed (576 in the buparlisib + fulvestrant and 571 in the placebo + fulvestrant arm). Not completed: in Randomization Phase=Randomized and not Treated; in Treatment Phase=Discontinued study treatment per Protocol.

    Period 1
    Period 1 title
    Randomization Phase
    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
    		 BKM120 100mg + Fulvestrant
    Arm description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to BKM120 100 mg once daily starting Cycle 1 Day 1

    Number of subjects in period 1
    		BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Started
    576
    571
    Safety Set (SS)
    573 [1]
    570
    Completed
    574
    569
    Not completed
    2
    2
         Adverse event, serious fatal
    -
    1
         Physician decision
    1
    1
         Adverse event, non-fatal
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Safety Set (SS) = At least 1 dose of study treatment and a 1 post baseline safety assessment
    Period 2
    Period 2 title
    Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BKM120 100mg + Fulvestrant
    Arm description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to BKM120 100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Number of subjects in period 2
    		BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Started
    574
    569
    BKM120 pharmacokinetic analysis set
    93
    0
    Full Pharmacokinetic Analysis Set (FPAS)
    35
    0
    Completed
    0
    0
    Not completed
    574
    569
         Adverse event, serious fatal
    6
    5
         Physician decision
    27
    24
         Consent withdrawn by subject
    55
    23
         Study terminated by Sponsor
    18
    15
         Adverse event, non-fatal
    80
    12
         Non-compliance with Study Treatment
    8
    1
         Lost to follow-up
    1
    -
         Disease Progression
    377
    486
         Protocol deviation
    2
    3
    Period 3
    Period 3 title
    Post-Treatment Efficacy Follow-Up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BKM120 100mg + Fulvestrant
    Arm description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Investigational medicinal product name
    Buparlisib
    Investigational medicinal product code
    BKM120
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily starting Cycle 1 Day 1

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to BKM120 100 mg once daily starting Cycle 1 Day 1

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg (Day 1 and Day 15 of Cycle 1 and Day 1 of every cycle thereafter)

    Number of subjects in period 3
    		BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Started
    89
    29
    Completed
    0
    0
    Not completed
    89
    29
         Adverse event, serious fatal
    4
    4
         Physician decision
    10
    3
         Consent withdrawn by subject
    11
    1
         Adverse event, non-fatal
    2
    -
         Disease Progression
    24
    8
         New therapy for study indication
    38
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.

    Reporting group values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant Total
    Number of subjects
    		 576 571 1147
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 329 378 707
        >=65 years
    		 247 193 440
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.2 ( 10.20 ) 60.6 ( 10.08 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 576 571 1147
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 132 153 285
        Black
    		 5 16 21
        Caucasian
    		 402 376 778
        Other
    		 18 7 25
        Unknown
    		 19 18 37
        Missing
    		 0 1 1
    ECOG Performance Status
    Units: Subjects
        Grade 0 = No Restrictions
    		 333 344 677
        Grade 1 = Only Light Work
    		 231 211 442
        Grade 2 = Only Self Care
    		 11 16 27
        Grade 3 = Only Limited Self-Care
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.
    Reporting group title
    BKM120 100mg + Fulvestrant
    Reporting group description
    		 BKM120 100 mg per day and fulvestrant given until progression or as described in the protocol.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 BKM120 matching placebo daily and fulvestrant given until progression or as described in the protocol.

    Primary: Progression Free Survival (PFS) based on Local Investigator assessment - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort

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    End point title
    		 Progression Free Survival (PFS) based on Local Investigator assessment - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort
    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 progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
    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 approximately 4 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    576
    571
    Units: Months
    median (confidence interval 95%)
        FAS-Full population
    6.9 (6.8 to 7.8)
    5.0 (4.0 to 5.2)
        FAS-Main cohort
    6.8 (5.0 to 7.0)
    4.5 (3.3 to 5.0)
        FAS-PI3K pathway activated
    6.8 (4.9 to 7.1)
    4.0 (3.1 to 5.2)
        FAS-PI3K pathway non-activated
    6.9 (4.6 to 7.2)
    4.6 (3.3 to 5.1)
        FAS-PI3K pathway unknown
    8.7 (7.0 to 12.4)
    6.8 (5.0 to 8.4)
    Statistical analysis title
    		 FAS-Full population
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 0.89
    Notes
    [1] - Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-Main cohort
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.003
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.94
    Notes
    [2] - Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-PI3K pathway activated
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.015
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.97
    Notes
    [3] - Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-PI3K pathway non-activated
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.03
    Notes
    [4] - Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-PI3K pathway unknown
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.94
    Notes
    [5] - Comparison of progression-free survival (PFS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance

    Secondary: Overall Survival (OS) - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort

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    End point title
    		 Overall Survival (OS) - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort
    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. Patients were followed up for the duration of the study and for an expected average of every 3 months after end of treatment.
    End point type
    Secondary
    End point timeframe
    Every 3 months following end of treatment visit, assessed for approximately 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    576
    571
    Units: Months
    median (confidence interval 95%)
        FAS-Full population
    33.2 (30.0 to 37.3)
    30.4 (27.9 to 32.2)
        FAS-Main cohort
    30.9 (25.1 to 35.4)
    28.9 (25.9 to 31.1)
        FAS-PI3K pathway activated
    33.6 (23.8 to 40.0)
    27.5 (24.4 to 31.3)
        FAS-PI3K pathway non-activated
    28.8 (23.0 to 33.2)
    30.0 (26.0 to 33.4)
        FAS-PI3K pathway unknown
    42.3 (36.5 to 999)
    36.0 (31.0 to 43.5)
    Statistical analysis title
    		 FAS-Full population
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.045
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.02
    Notes
    [6] - Comparison of overall survival (OS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-Main cohort
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.144
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.09
    Notes
    [7] - Comparison of overall survival (OS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-PI3K pathway activated
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.08
    Notes
    [8] - Comparison of overall survival (OS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-PI3K pathway non-activated
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.24
    Notes
    [9] - Comparison of overall survival (OS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance
    Statistical analysis title
    		 FAS-PI3K pathway unknown
    Comparison groups
    BKM120 100mg + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    1147
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.06
    Notes
    [10] - Comparison of overall survival (OS) (based on local investigator assessment) between the two treatment groups using a stratified log-rank test at one-sided 2.5% level of significance

    Secondary: Overall Response Rate (ORR) - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort

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    End point title
    		 Overall Response Rate (ORR) - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort
    End point description
    Overall Response Rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator’s assessment according to RECIST 1.1. ORR was analyzed in the full population. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Only descriptive analysis performed.
    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 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    576
    571
    Units: Percentage of Participants
    number (confidence interval 95%)
        FAS-Full population
    11.8 (9.3 to 14.7)
    7.7 (5.7 to 10.2)
        FAS-Main cohort
    11.0 (8.2 to 14.4)
    7.8 (5.4 to 10.8)
        FAS-PI3K pathway activated
    10.6 (6.6 to 16.0)
    8.2 (4.6 to 13.1)
        FAS-PI3K pathway non-activated
    11.3 (7.6 to 16.0)
    7.5 (4.5 to 11.6)
        FAS-PI3K pathway unknown
    14.1 (8.9 to 20.7)
    7.5 (3.8 to 13.0)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort

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    End point title
    		 Clinical Benefit Rate (CBR) - Full Analysis Set (FAS) in Full population, Main Study Cohort and PI3K unknown cohort
    End point description
    Clinical Benefit Rate (CBR) is defined as the percentage 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. CBR was analyzed in the full population. Only descriptive analysis performed.
    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 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    576
    571
    Units: Percentage of Participants
    number (confidence interval 95%)
        FAS-Full population
    43.8 (39.7 to 47.9)
    42.0 (37.9 to 46.2)
        FAS-Main cohort
    41.7 (37.0 to 46.5)
    39.6 (34.9 to 44.5)
        FAS-PI3K pathway activated
    40.4 (33.3 to 47.8)
    40.8 (33.6 to 48.2)
        FAS-PI3K pathway non-activated
    42.7 (36.3 to 49.2)
    38.8 (32.6 to 45.2)
        FAS-PI3K pathway unknown
    49.7 (41.4 to 58.0)
    49.0 (40.7 to 57.3)
    No statistical analyses for this end point

    Secondary: Number of Participants with On-Treatments Adverse Events, Serious Adverse Events and Deaths

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    End point title
    		 Number of Participants with On-Treatments Adverse Events, Serious Adverse Events and Deaths
    End point description
    Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment to 30 days after last dose of study treatment, assessed for approximately 5 years
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    573
    570
    Units: Percentage of Participants
    number (not applicable)
        On-treatment Adverse Event (AEs)
    99.3
    93.3
        On-treatment Serious Adverse Event (SAEs)
    25.5
    17.7
        On-treatment Deaths
    2.1
    2.3
        Primary cause of Death = Study Indication
    1.0
    1.2
        Primary cause of Death = Unknown reason
    0.3
    0
        Primary cause of Death = Disease Progression
    0.3
    0.4
        Primary cause of Death = Pneumonia
    0.2
    0
        Primary cause of Death = Septic Shock
    0.2
    0
        Primary cause of Death = Cerebral Haemorrhage
    0
    0.2
        Primary cause of Death = Cerebral Accident
    0
    0.2
        Primary cause of Death = Sudden Death
    0
    0.2
        Primary cause of Death = Urosepsis
    0
    0.2
    No statistical analyses for this end point

    Secondary: Plasma concentration-time profiles of BKM120 in combination with Fulvestrant at Cycle 2 Day 1

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    End point title
    		 Plasma concentration-time profiles of BKM120 in combination with Fulvestrant at Cycle 2 Day 1 [11]
    End point description
    Plasma samples were collected from the first 200 BKM120-treated patients on Cycle 2 Day 1 (at pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h [before Cycle 2 Day 2 dose] post-dose). Each cycle is 28 days. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Cycle2 Day1 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours post-dose). Each cycle is 28 days.
    Notes
    [11] - 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: BKM120 PK sampling only performed in BKM120 100mg + Fulvestrant treatment arm
    End point values
    		 BKM120 100mg + Fulvestrant
    Number of subjects analysed
    35
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        C2D1 0hr (predose)
    768.306 ( 69.1 )
        C2D1 0.5hr
    750.767 ( 55.4 )
        C2D1 1hr
    988.341 ( 49.2 )
        C2D1 1.5hr
    1082.086 ( 45.0 )
        C2D1 2hr
    1099.517 ( 36.4 )
        C2D1 3hr
    1081.123 ( 43.2 )
        C2D1 4hr
    935.485 ( 43.0 )
        C2D1 6hr
    795.555 ( 45.1 )
        C2D1 8hr
    808.886 ( 50.5 )
        C2D1 24hr
    712.336 ( 52.7 )
    No statistical analyses for this end point

    Secondary: Predose trough concentration-time profile of BKM120 in combination with Fulvestrant over time - Pharmacokinetic Analysis Set (PAS)

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    End point title
    		 Predose trough concentration-time profile of BKM120 in combination with Fulvestrant over time - Pharmacokinetic Analysis Set (PAS) [12]
    End point description
    Pre-dose samples were collected for trough concentrations at Cycle 2 Day 1, Cycle 2 Day 15 and Cycle 3 Day 1. Each cycle is 28 days. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1. Each cycle is 28 days.
    Notes
    [12] - 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: BKM120 PK sampling only performed in BKM120 100mg + Fulvestrant treatment arm
    End point values
    		 BKM120 100mg + Fulvestrant
    Number of subjects analysed
    93
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1
    733.278 ( 75.6 )
        Cycle 2 Day 15
    735.172 ( 51.2 )
        Cycle 3 Day 1
    716.414 ( 84.8 )
    No statistical analyses for this end point

    Secondary: Median time to definitive deterioration of the ECOG performance status - Full Analysis Set (FAS)

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    End point title
    		 Median time to definitive deterioration of the ECOG performance status - Full Analysis Set (FAS)
    End point description
    Time to definitive deterioration of the ECOG PS was defined as the time between the date of randomization and the date of the assessment at which definitive deterioration was seen. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Up to approx 27 months
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    576
    571
    Units: Months
        median (confidence interval 95%)
    24.0 (17.1 to 999)
    26.4 (19.9 to 999)
    No statistical analyses for this end point

    Secondary: Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30

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    End point title
    		 Health-related quality of life (HRQoL):Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30
    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 defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL. Patients were assessed up to approx. 8.3 months. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1, cycle 1 day 15, 6 weeks after randomisation and then every 8 weeks until end of treatment
    End point values
    		 BKM120 100mg + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    576
    571
    Units: Months
        median (confidence interval 95%)
    7.10 (6.01 to 9.82)
    11.50 (8.80 to 14.32)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 70 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo@+ fulvestrant
    Reporting group description
    		 Placebo@+ fulvestrant

    Reporting group title
    BKM120 100 mg@+ fulvestrant
    Reporting group description
    		 BKM120 100 mg@+ fulvestrant

    Serious adverse events
    		 Placebo@+ fulvestrant BKM120 100 mg@+ fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 570 (17.72%)
    146 / 573 (25.48%)
         number of deaths (all causes)
    13
    12
         number of deaths resulting from adverse events
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 570 (0.35%)
    7 / 573 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Breakthrough pain
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Disease progression
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 570 (0.00%)
    7 / 573 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    2 / 570 (0.35%)
    6 / 573 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 6
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Incarcerated hernia
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 570 (0.35%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 570 (0.53%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         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
    Asthma
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 570 (0.53%)
    4 / 573 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea at rest
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 570 (1.40%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 570 (0.00%)
    4 / 573 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 570 (0.18%)
    17 / 573 (2.97%)
         occurrences causally related to treatment / all
    0 / 1
    15 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 570 (0.18%)
    14 / 573 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 570 (0.18%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (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 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 570 (0.53%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 570 (0.35%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (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 haemorrhage
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 570 (0.53%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coordination abnormal
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    3 / 570 (0.53%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movement disorder
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (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
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 570 (0.35%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 570 (0.70%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 570 (0.53%)
    4 / 573 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (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
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 570 (0.35%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 570 (0.53%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 570 (0.35%)
    7 / 573 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 570 (0.35%)
    4 / 573 (0.70%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 570 (0.53%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 570 (0.18%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 570 (0.88%)
    7 / 573 (1.22%)
         occurrences causally related to treatment / all
    2 / 5
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (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
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 570 (0.00%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 570 (0.18%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 570 (0.35%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 570 (0.00%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 570 (0.53%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 570 (0.53%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cellulitis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 570 (0.00%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 570 (0.00%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 570 (0.35%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 570 (0.88%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pyelonephritis
         subjects affected / exposed
    2 / 570 (0.35%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyuria
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 570 (0.18%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 570 (0.18%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Soft tissue infection
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 570 (0.18%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 570 (0.35%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral labyrinthitis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Decreased appetite
         subjects affected / exposed
    0 / 570 (0.00%)
    3 / 573 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 570 (0.00%)
    5 / 573 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 570 (0.18%)
    2 / 573 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 570 (0.00%)
    11 / 573 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 573 (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
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 573 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo@+ fulvestrant BKM120 100 mg@+ fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    485 / 570 (85.09%)
    560 / 573 (97.73%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 570 (6.84%)
    229 / 573 (39.97%)
         occurrences all number
    55
    280
    Aspartate aminotransferase increased
         subjects affected / exposed
    55 / 570 (9.65%)
    217 / 573 (37.87%)
         occurrences all number
    76
    282
    Blood alkaline phosphatase increased
         subjects affected / exposed
    31 / 570 (5.44%)
    40 / 573 (6.98%)
         occurrences all number
    36
    49
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    39 / 570 (6.84%)
    45 / 573 (7.85%)
         occurrences all number
    41
    54
    Weight decreased
         subjects affected / exposed
    24 / 570 (4.21%)
    84 / 573 (14.66%)
         occurrences all number
    25
    89
    Vascular disorders
    Hot flush
         subjects affected / exposed
    53 / 570 (9.30%)
    33 / 573 (5.76%)
         occurrences all number
    60
    36
    Hypertension
         subjects affected / exposed
    29 / 570 (5.09%)
    57 / 573 (9.95%)
         occurrences all number
    37
    81
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 570 (5.26%)
    75 / 573 (13.09%)
         occurrences all number
    34
    99
    Dysgeusia
         subjects affected / exposed
    22 / 570 (3.86%)
    84 / 573 (14.66%)
         occurrences all number
    26
    97
    Headache
         subjects affected / exposed
    79 / 570 (13.86%)
    88 / 573 (15.36%)
         occurrences all number
    112
    117
    Tremor
         subjects affected / exposed
    7 / 570 (1.23%)
    44 / 573 (7.68%)
         occurrences all number
    8
    52
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    51 / 570 (8.95%)
    38 / 573 (6.63%)
         occurrences all number
    71
    52
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    62 / 570 (10.88%)
    113 / 573 (19.72%)
         occurrences all number
    75
    148
    Fatigue
         subjects affected / exposed
    143 / 570 (25.09%)
    187 / 573 (32.64%)
         occurrences all number
    167
    234
    Injection site pain
         subjects affected / exposed
    34 / 570 (5.96%)
    27 / 573 (4.71%)
         occurrences all number
    43
    35
    Oedema peripheral
         subjects affected / exposed
    30 / 570 (5.26%)
    38 / 573 (6.63%)
         occurrences all number
    36
    49
    Pyrexia
         subjects affected / exposed
    22 / 570 (3.86%)
    44 / 573 (7.68%)
         occurrences all number
    24
    51
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    30 / 570 (5.26%)
    40 / 573 (6.98%)
         occurrences all number
    45
    47
    Abdominal pain upper
         subjects affected / exposed
    38 / 570 (6.67%)
    46 / 573 (8.03%)
         occurrences all number
    43
    50
    Constipation
         subjects affected / exposed
    71 / 570 (12.46%)
    68 / 573 (11.87%)
         occurrences all number
    83
    90
    Diarrhoea
         subjects affected / exposed
    84 / 570 (14.74%)
    198 / 573 (34.55%)
         occurrences all number
    111
    294
    Dry mouth
         subjects affected / exposed
    20 / 570 (3.51%)
    46 / 573 (8.03%)
         occurrences all number
    22
    49
    Dyspepsia
         subjects affected / exposed
    25 / 570 (4.39%)
    52 / 573 (9.08%)
         occurrences all number
    27
    57
    Nausea
         subjects affected / exposed
    138 / 570 (24.21%)
    227 / 573 (39.62%)
         occurrences all number
    188
    299
    Stomatitis
         subjects affected / exposed
    40 / 570 (7.02%)
    124 / 573 (21.64%)
         occurrences all number
    43
    166
    Vomiting
         subjects affected / exposed
    79 / 570 (13.86%)
    92 / 573 (16.06%)
         occurrences all number
    123
    116
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    69 / 570 (12.11%)
    76 / 573 (13.26%)
         occurrences all number
    78
    91
    Dyspnoea
         subjects affected / exposed
    56 / 570 (9.82%)
    44 / 573 (7.68%)
         occurrences all number
    67
    52
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    20 / 570 (3.51%)
    41 / 573 (7.16%)
         occurrences all number
    22
    47
    Dry skin
         subjects affected / exposed
    17 / 570 (2.98%)
    69 / 573 (12.04%)
         occurrences all number
    21
    77
    Pruritus
         subjects affected / exposed
    33 / 570 (5.79%)
    88 / 573 (15.36%)
         occurrences all number
    41
    116
    Rash
         subjects affected / exposed
    39 / 570 (6.84%)
    187 / 573 (32.64%)
         occurrences all number
    46
    273
    Rash maculo-papular
         subjects affected / exposed
    8 / 570 (1.40%)
    39 / 573 (6.81%)
         occurrences all number
    8
    48
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    53 / 570 (9.30%)
    129 / 573 (22.51%)
         occurrences all number
    64
    164
    Depression
         subjects affected / exposed
    56 / 570 (9.82%)
    152 / 573 (26.53%)
         occurrences all number
    75
    202
    Insomnia
         subjects affected / exposed
    50 / 570 (8.77%)
    60 / 573 (10.47%)
         occurrences all number
    51
    62
    Mood altered
         subjects affected / exposed
    17 / 570 (2.98%)
    40 / 573 (6.98%)
         occurrences all number
    18
    43
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    74 / 570 (12.98%)
    62 / 573 (10.82%)
         occurrences all number
    102
    75
    Back pain
         subjects affected / exposed
    72 / 570 (12.63%)
    66 / 573 (11.52%)
         occurrences all number
    89
    78
    Bone pain
         subjects affected / exposed
    34 / 570 (5.96%)
    38 / 573 (6.63%)
         occurrences all number
    41
    44
    Muscle spasms
         subjects affected / exposed
    21 / 570 (3.68%)
    32 / 573 (5.58%)
         occurrences all number
    23
    41
    Musculoskeletal pain
         subjects affected / exposed
    40 / 570 (7.02%)
    27 / 573 (4.71%)
         occurrences all number
    48
    30
    Pain in extremity
         subjects affected / exposed
    61 / 570 (10.70%)
    51 / 573 (8.90%)
         occurrences all number
    81
    66
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 570 (5.44%)
    29 / 573 (5.06%)
         occurrences all number
    34
    31
    Urinary tract infection
         subjects affected / exposed
    31 / 570 (5.44%)
    46 / 573 (8.03%)
         occurrences all number
    40
    60
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    68 / 570 (11.93%)
    174 / 573 (30.37%)
         occurrences all number
    74
    208
    Hyperglycaemia
         subjects affected / exposed
    46 / 570 (8.07%)
    244 / 573 (42.58%)
         occurrences all number
    81
    408
    Hypokalaemia
         subjects affected / exposed
    13 / 570 (2.28%)
    41 / 573 (7.16%)
         occurrences all number
    21
    56

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2013
    1) A higher than expected rate of patients were randomized with PI3K pathway status unknown (approximately 25% as compared to initial assumptions of 10%). Study design, primary endpoints, statistical and biomarker sections were modified due to higher incidence of the unknown PI3K pathway status patients, and to mitigate the impact on the overall analysis. 2) In addition, futility rule at interim look was modified to be more aggressive in order to increase the probability to stop the study at the interim look if the null hypothesis based on the Main study cohort was true, while maintaining a good level of power; PK analysis was clarified and modifications to the management of psychiatric disorders (follow up advisory board), stomatitis and rash were made. 3) PI3K pathway activation status (one of the two stratification factors) definition was modified to exclude PTEN gene mutation (exon 4). Considering the very small number of ER+ breast cancer patients expected to display mutation of the PTEN gene (<2%) this analysis was performed in an exploratory fashion. 4) In view of positive data published on the potential utility for circulating DNA to detect mutations in the PI3K related pathway genes in MBC, blood collection at entry on study for mutation analysis in circulating DNA was made mandatory. 5) Clarifications were made with respect to PK analysis and modifications to the management of psychiatric disorders (follow up advisory board), stomatitis and rash were made. 6) Other changes for clarification purpose included pregnancy testing requirement, definition of post-menopausal status, fulvestrant discontinuation criteria, ECG parameters, protocol window for signed informed consent and shipment of tumor sample, as well as editorial changes.
    30 May 2013
    1) To update and align the management of selected AEs across the buparlisib program (e.g. transaminases increase, grade 2 hyperglycemia). 2) To increase the AEs recovery time period by increasing the maximum allowed treatment interruption for buparlisib/placebo from 21 to 28 days. 3) Weekly monitoring of hematology and partial biochemistry parameters (AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin and creatinine) during the first two cycles of study treatment starting from Cycle 1 Day 15 to allow early patients safety management. 4) Changes in eligibility criteria, inclusion criteria were revised to: * Allow inclusion of patients with prior documentation of PI3K pathway results through a Novartis central laboratory and adequate tumor tissue. * Clarify that postmenopausal range for hormone levels was either serum FSH >40 mIU/mL and estradiaol <20 pg/mL, or according to the respective postmenopausal range definition used by the local laboratory involved. * Allow patients with AST/ALT/total bilirubin values below to the lower limit of normal because these patients were suitable to participate in the study. 5) The PI3K pathway activation status definition was modified and no longer included PIK3CA mutations in exon 5 which were very rare in breast cancer. 6) Time to deterioration of ECOG performance status was added as a secondary objective to support the assessment of clinical benefit.
    31 Jul 2014
    The amendment ensured the generalizability of the results to the entire randomized population. 1) Full population was defined as Main study cohort + PI3K unknown cohort, 2) The primary hypothesis of interest was modified with the addition of PFS and OS in Full population as primary and key-secondary endpoints. There were three populations of interest: i) Main cohort and/or ii) Full population or iii) PI3K activated subpopulation, 3) The gatekeeping procedure was modified so that a formal statistical test can be used to test PFS/OS in the Full population, 4) The final OS analysis will be driven by the observed number of deaths in the Full population, 5) The ORR, CBR, ECOG, HRQoL analysis will also be done in the Full population. In addition following changes were made: 1) Clarification was provided that at the time of final PFS analyses, both PFS and interim OS analysis will be performed by the Sponsor's clinical team. Investigators and patients will remain blinded to study treatment and all patients will continue to be followed for OS until the final OS analysis (or earlier if OS reaches statistical significance at the interim analyses). 2) Collection of blood samples for CTCs was stopped in the study at Baseline and following treatment (Cycle 3 Day 1) for an exploratory analysis. 3) Co-administration of weak and moderate inducers and inhibitors with buparlisib was permitted during the course of the study as per the Investigator’s Brochure (version 6). Strong inhibitors and inducers remain prohibited. 4) Moderate doses of corticosteroids equivalent to up to 4 mg once daily of dexamethasone were allowed. 5) Changes in safety management were made as per Investigator’s Brochure (version 6).
    23 Jul 2015
    1) Additional guidance was provided to Investigators around management of liver toxicity: During the search for potential drug-induced liver injury (DILI) cases in buparlisib Novartis-sponsored trials, few cases of DILI cases were consistent with the Hy’s law criteria. Hence the liver-related safety measures were updated in ongoing protocols to enhance patient safety. 2) Clarification was provided for, study treatment discontinuation, lost to follow-up, and withdrawal of consent. 3) Clarification for requirements for efficacy, safety and patient-reported outcomes (PRO) assessments were provided after final PFS analysis.
    22 Jun 2016
    The key features of this amendment were: 1) Provided a clarification on the measures to follow when a patient exhibited suicidal ideation regardless of the response to question 9 of the Patient Health Questionnaire (PHQ-9) questionnaire. 2) After the final OS analysis, unblinding occurred. The frequency of study evaluations was reduced and standard of care was followed while maintaining the key safety assessments. The patients continued to receive treatment with buparlisib and/or fulvestrant until either progression of disease, unacceptable toxicities, withdrawal of patient consent, physician decision or discontinuation of buparlisib development by Novartis, whichever occurred earlier. Patients considered to be benefiting from study treatment per investigator assessment could be eligible to continue to receive study treatment. 3) After the final OS analysis, tumor evaluation was performed as per standard of care and survival follow up was not performed.

    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.
    Novartis made the decision not to pursue further development of buparlisib and to terminate the ongoing studies in Breast Cancer. The CBKM120F2302 study was terminated on 19-Apr-2019 (last subject last visit).
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