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    Clinical Trial Results:
    SOLAR-1: A Phase III randomized double-blind, placebo controlled study of alpelisib in combination with fulvestrant for men and postmenopausal women with hormone receptor positive, HER2-negative advanced breast cancer which progressed on or after aromatase inhibitor treatment

    Summary
    EudraCT number
    		 2015-000340-42
    Trial protocol
    		 DE   SE   AT   NL   CZ   HU   IT   BE   FR   ES   GR   GB   BG   PT   DK  
    Global end of trial date
    09 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jun 2024
    First version publication date
    12 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBYL719C2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02437318
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus,, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine whether treatment with alpelisib in combination with fulvestrant prolongs progression-free survival (PFS) based on local investigator assessment compared to treatment with placebo in combination with fulvestrant for subjects with advanced breast cancer with a PIK3CA mutation.
    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
    23 Jul 2015
    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: 10
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Chile: 11
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    India: 6
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 68
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Lebanon: 8
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Peru: 11
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Spain: 65
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    572
    EEA total number of subjects
    280
    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)
    321
    From 65 to 84 years
    246
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in 198 centers across 31 countries

    Pre-assignment
    Screening details
    		 One subject in the PIK3CA mutant cohort, who was randomized to the placebo + fulvestrant arm, did not receive study treatment due to a protocol deviation.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alpelisib + fulvestrant
    Arm description
    		 Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alpelisib
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg of alpelisib tablets for oral use administered once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets for oral use administered once daily

    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 of fulvestrant administered via intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle

    Arm title
    		 Placebo + fulvestrant
    Arm description
    		 Subjects treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
    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 of fulvestrant administered via intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle

    Number of subjects in period 1
    		Alpelisib + fulvestrant Placebo + fulvestrant
    Started
    284
    288
    Treated
    284
    287
    PIK3CA mutant cohort by tumor tissue
    169
    172
    PIK3CA non-mutant cohort by tumor tissue
    115
    116
    PIK3CA mutant cohort by ctDNA
    92
    94
    PIK3CA non-mutant cohort by ctDNA
    181
    182
    Completed
    0
    0
    Not completed
    284
    288
         Adverse event, serious fatal
    4
    4
         Physician decision
    29
    22
         Adverse event, non-fatal
    14
    4
         Protocol deviation
    5
    7
         Study terminated by sponsor
    1
    -
         Progressive disease
    207
    240
         Subject/guardian decision
    24
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alpelisib + fulvestrant
    Reporting group description
    		 Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Reporting group title
    Placebo + fulvestrant
    Reporting group description
    		 Subjects treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Reporting group values
    		 Alpelisib + fulvestrant Placebo + fulvestrant Total
    Number of subjects
    		 284 288 572
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 167 154 321
        From 65-84 years
    		 116 130 246
        85 years and over
    		 1 4 5
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.6 ( 9.74 ) 63.3 ( 10.26 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 283 288 571
        Male
    		 1 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 199 178 377
        Asian
    		 59 66 125
        Black or African American
    		 2 6 8
        American Indian or Alaska
    		 1 4 5
        Other
    		 9 17 26
        Unknown
    		 14 17 31
    Subject analysis sets

    Subject analysis set title
    PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant determined by ctDNA: alpelisib + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (measured in ctDNA) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant determined by ctDNA: placebo + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (measured in ctDNA) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant determined by ctDNA: alpelisib + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (measured in ctDNA) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant determined by ctDNA: placebo + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (measured in ctDNA) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis sets values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant PIK3CA mutant determined by ctDNA: alpelisib + fulvestrant PIK3CA mutant determined by ctDNA: placebo + fulvestrant PIK3CA non-mutant determined by ctDNA: alpelisib + fulvestrant PIK3CA non-mutant determined by ctDNA: placebo + fulvestrant
    Number of subjects
    169
    172
    115
    116
    92
    94
    181
    182
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    11.0 ( )
    5.7 ( )
    7.43 ( )
    7.23 ( )
    10.9 ( )
    3.7 ( )
    9.0 ( )
    7.4 ( )
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
        Asian
        Black or African American
        American Indian or Alaska
        Other
        Unknown

    End points

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    End points reporting groups
    Reporting group title
    Alpelisib + fulvestrant
    Reporting group description
    		 Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Reporting group title
    Placebo + fulvestrant
    Reporting group description
    		 Subjects treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant determined by ctDNA: alpelisib + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (measured in ctDNA) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA mutant determined by ctDNA: placebo + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer with a PIK3CA mutation (measured in ctDNA) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant determined by ctDNA: alpelisib + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (measured in ctDNA) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Subject analysis set title
    PIK3CA non-mutant determined by ctDNA: placebo + fulvestrant
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with advanced breast cancer without a PIK3CA mutation (measured in ctDNA) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)

    Primary: Progression-free survival (PFS) per Investigator assessment in the PIK3CA mutant cohort

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    End point title
    		 Progression-free survival (PFS) per Investigator assessment in the PIK3CA mutant cohort
    End point description
    PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Progression was defined as at least a 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. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Primary
    End point timeframe
    Once approximately 243 PFS events in the PIK3CA mutant cohort had been observed, up to 33.3 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant
    Number of subjects analysed
    169
    172
    Units: Months
        median (confidence interval 95%)
    11.0 (7.49 to 14.52)
    5.7 (3.65 to 7.36)
    Statistical analysis title
    		 PFS analysis
    Comparison groups
    PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant v PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00065 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.85
    Notes
    [1] - (one-sided)

    Secondary: Overall survival (OS) in the PIK3CA mutant cohort

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    End point title
    		 Overall survival (OS) in the PIK3CA mutant cohort
    End point description
    OS was 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, survival was censored at the date of last known date patient alive. The OS distribution was estimated using Kaplan-Meier methodology.
    End point type
    Secondary
    End point timeframe
    Once approximately 178 deaths in the PIK3CA mutant cohort had been observed, up to 55.7 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant
    Number of subjects analysed
    169
    172
    Units: Months
        median (confidence interval 95%)
    39.3 (34.10 to 44.85)
    31.4 (26.78 to 41.30)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) per Investigator assessment

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    End point title
    		 Overall response rate (ORR) per Investigator assessment
    End point description
    ORR was defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator’s assessment according to RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Up to 56.4 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    169
    172
    115
    116
    Units: Percentage of participants
        number (confidence interval 95%)
    26.6 (20.1 to 34.0)
    13.4 (8.7 to 19.4)
    20.9 (13.9 to 29.4)
    12.9 (7.4 to 20.4)
    No statistical analyses for this end point

    Secondary: OS in the PIK3CA non-mutant cohort

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    End point title
    		 OS in the PIK3CA non-mutant cohort
    End point description
    OS was 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, survival was censored at the date of last known date patient alive. The OS distribution was estimated using Kaplan-Meier methodology.
    End point type
    Secondary
    End point timeframe
    Up to 56.4 months
    End point values
    		 PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    115
    116
    Units: Months
        median (confidence interval 95%)
    37.29 (27.89 to 45.47)
    34.30 (26.81 to 39.03)
    No statistical analyses for this end point

    Secondary: PFS per investigator assessment in the PIK3CA non-mutant cohort

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    End point title
    		 PFS per investigator assessment in the PIK3CA non-mutant cohort
    End point description
    PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Progression was defined as at least a 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. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    Up to 56.4 months
    End point values
    		 PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    115
    116
    Units: Months
        median (confidence interval 95%)
    7.43 (5.55 to 10.84)
    7.23 (5.06 to 9.17)
    No statistical analyses for this end point

    Secondary: Clinical benefit rate (CBR) per Investigator assessment

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    End point title
    		 Clinical benefit rate (CBR) per Investigator assessment
    End point description
    Clinical benefit rate was defined as the percentage of patients with a best overall response of CR or PR or stable disease (SD) or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment according to RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    Up to 56.4 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    169
    172
    115
    116
    Units: Percentage of participants
        number (confidence interval 95%)
    61.5 (53.8 to 68.9)
    44.8 (37.2 to 52.5)
    53.9 (44.4 to 63.2)
    49.1 (39.7 to 58.6)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) score from baseline

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    End point title
    		 Time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) score from baseline
    End point description
    ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration of ECOG PS by one score was defined as the time from the date of randomization to the date of the event, defined as experiencing at least one score lower than the baseline. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment. 9999 indicates that the value was not estimable.
    End point type
    Secondary
    End point timeframe
    From baseline up to 56.4 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    169
    172
    115
    116
    Units: Months
        median (confidence interval 95%)
    34.07 (26.32 to 9999)
    9999 (22.11 to 9999)
    9999 (13.83 to 9999)
    40.44 (18.46 to 47.21)
    No statistical analyses for this end point

    Secondary: Time to 10% deterioration in the global health status (GHS) /Quality of Life (QOL) scale score of the European Organization for Research and Treatment of Cancer’s core quality of life questionnaire (EORTC QLQ-C30)

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    End point title
    		 Time to 10% deterioration in the global health status (GHS) /Quality of Life (QOL) scale score of the European Organization for Research and Treatment of Cancer’s core quality of life questionnaire (EORTC QLQ-C30)
    End point description
    The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as at least 10% relative to baseline worsening of the GHS/QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From baseline up to 55.7 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    169
    172
    115
    116
    Units: Months
        median (confidence interval 95%)
    18.14 (14.55 to 28.68)
    19.98 (11.50 to 25.59)
    7.39 (5.62 to 9999)
    9.23 (3.94 to 13.17)
    No statistical analyses for this end point

    Secondary: Change from baseline in the GHS/QOL scale score of the EORTC QLQ-C30

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    End point title
    		 Change from baseline in the GHS/QOL scale score of the EORTC QLQ-C30
    End point description
    The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicated improvement. For each cohort, this analysis only included assessments up to the time point where there were at least 10 patients on each of the 2 treatment groups. 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks after randomization during the first 18 months and thereafter every 12 weeks, up to 120 weeks.
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant PIK3CA non-mutant cohort by tumor tissue:alpelisib+fulvestrant PIK3CA non-mutant cohort by tumor tissue:placebo+fulvestrant
    Number of subjects analysed
    142
    140
    98
    92
    Units: Score on a Scale
    least squares mean (standard error)
        Week 8 (n=142 / 140 / 98 / 92)
    -2.477 ( 2.286 )
    -0.369 ( 2.324 )
    1.524 ( 2.578 )
    2.698 ( 2.601 )
        Week 16 (n=124 / 107 / 66 / 66)
    -1.796 ( 2.349 )
    -2.685 ( 2.455 )
    2.866 ( 2.809 )
    1.700 ( 2.835 )
        Week 24 (n=105 / 81 / 46 / 34)
    -3.010 ( 2.415 )
    -0.337 ( 2.587 )
    1.383 ( 3.087 )
    4.909 ( 3.385 )
        Week 32 (n=86 / 73 / 32 / 25)
    -2.802 ( 2.519 )
    -0.891 ( 2.646 )
    1.063 ( 3.420 )
    4.345 ( 3.731 )
        Week 40 (n=75 / 62 / 12 / 20)
    -2.815 ( 2.581 )
    -1.854 ( 2.739 )
    13.232 ( 4.783 )
    4.923 ( 4.003 )
        Week 48 (n=69 / 51 / 0 / 0)
    -3.635 ( 2.621 )
    -1.460 ( 2.853 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 56 (n=59 / 45 / 0 / 0)
    -1.617 ( 2.701 )
    0.248 ( 2.935 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 64 (n=47 / 42 / 0 / 0)
    -1.937 ( 2.835 )
    -1.979 ( 2.984 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 72 (n=48 / 36 / 0 / 0)
    -2.525 ( 2.823 )
    -1.526 ( 3.098 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 84 (n=40 / 34 / 0 / 0)
    -1.135 ( 2.958 )
    -1.495 ( 3.143 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 96 (n=35/ 25 / 0 / 0)
    -3.869 ( 3.054 )
    -3.581 ( 3.423 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 108 (n=26 / 21 / 0 / 0)
    -2.158 ( 3.328 )
    -2.068 ( 3.609 )
    9999 ( 9999 )
    9999 ( 9999 )
        Week 120 (n=28 / 17 / 0 / 0)
    -2.928 ( 3.251 )
    -2.593 ( 3.868 )
    9999 ( 9999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Trough plasma concentration of alpelisib

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    End point title
    		 Trough plasma concentration of alpelisib [2]
    End point description
    Pre-dose plasma concentrations of alpelisib were assessed. Only participants randomized to the alpelisib + fulvestrant arm were included in this analysis.
    End point type
    Secondary
    End point timeframe
    Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2, 4, 6 and 8. Cycle = 28 days
    Notes
    [2] - 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: Only participants who were randomized to receive alpelisib were included in this analysis.
    End point values
    		 Alpelisib + fulvestrant
    Number of subjects analysed
    96
    Units: nanogram (ng)/ milliliter (mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 8
    424 ( 41.1 )
        Cycle 1 Day 15
    468 ( 57.6 )
        Cycle 2 Day 1
    436 ( 53.4 )
        Cycle 4 Day 1
    458 ( 69.4 )
        Cycle 6 Day 1
    418 ( 57.1 )
        Cycle 8 Day 1
    469 ( 58.3 )
    No statistical analyses for this end point

    Secondary: Trough plasma concentration of fulvestrant

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    End point title
    		 Trough plasma concentration of fulvestrant
    End point description
    Pre-dose plasma concentrations of fulvestrant were assessed.
    End point type
    Secondary
    End point timeframe
    Day 15 of Cycle 1, then Day 1 of Cycles 2, 4, 6 and 8. Cycle = 28 days
    End point values
    		 Alpelisib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    124
    124
    Units: nanogram (ng)/ milliliter (mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 15
    10.8 ( 43.5 )
    10.3 ( 51.0 )
        Cycle 2 Day 1
    14.0 ( 39.7 )
    14.7 ( 41.2 )
        Cycle 4 Day 1
    11.5 ( 32.2 )
    12.2 ( 29.8 )
        Cycle 6 Day 1
    12.6 ( 30.5 )
    14.0 ( 24.2 )
        Cycle 8 Day 1
    13.5 ( 35.2 )
    14.7 ( 23.2 )
    No statistical analyses for this end point

    Secondary: PFS per investigator criteria in subjects with PIK3CA mutation status measured in ctDNA at baseline

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    End point title
    		 PFS per investigator criteria in subjects with PIK3CA mutation status measured in ctDNA at baseline
    End point description
    PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Subjects were analyzed according to the PIK3CA mutation status (mutant or non-mutant) as identified using plasma ctDNA. Progression was defined as at least a 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. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    From baseline up to 56.4 months
    End point values
    		 PIK3CA mutant determined by ctDNA: alpelisib + fulvestrant PIK3CA mutant determined by ctDNA: placebo + fulvestrant PIK3CA non-mutant determined by ctDNA: alpelisib + fulvestrant PIK3CA non-mutant determined by ctDNA: placebo + fulvestrant
    Number of subjects analysed
    92
    94
    181
    182
    Units: Months
        median (confidence interval 95%)
    10.9 (7.03 to 15.28)
    3.7 (2.27 to 6.11)
    9.0 (7.23 to 11.01)
    7.4 (5.55 to 9.20)
    No statistical analyses for this end point

    Other pre-specified: Updated PFS per Investigator assessment in the PIK3CA mutant cohort (longer follow-up)

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    End point title
    		 Updated PFS per Investigator assessment in the PIK3CA mutant cohort (longer follow-up)
    End point description
    PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. This analysis was conducted at the time of the final OS analysis (when approximately 178 deaths in the PIK3CA mutant cohort had been achieved) and includes a longer follow-up time. Progression was defined as at least a 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. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Other pre-specified
    End point timeframe
    Up to 55.7 months
    End point values
    		 PIK3CA mutant cohort by tumor tissue: alpelisib + fulvestrant PIK3CA mutant cohort by tumor tissue: placebo + fulvestrant
    Number of subjects analysed
    169
    172
    Units: Months
        median (confidence interval 95%)
    10.97 (7.49 to 14.52)
    5.65 (3.65 to 7.36)
    No statistical analyses for this end point

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    Pre-treatment deaths were collected from day of participant’s informed consent to the day before first dose of study medication. On-treatment deaths were collected from start of treatment to 30 days after last dose of study medication. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study treatment to end of study.
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment: Up to 35 days prior to treatment. On-treatment: Up to approx. 6.5 years. Post-treatment survival follow-up: Up to approx. 6.5 years
    End point values
    		 Alpelisib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    284
    288
    Units: Participants
        Pre-treatment
    0
    0
        On-treatment
    9
    12
        Post-treatment survival follow-up
    151
    156
        All deaths
    160
    168
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment to 30 days after last dose of treatment, up to approx. 6.5 years.
    Adverse event reporting additional description
    Consistent with EudraCTdisclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting fromadverse 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
    26.0
    Reporting groups
    Reporting group title
    Placebo + fulvestrant (on-treatment)
    Reporting group description
    		 AEs collected during on-treatment period (up to 30 days post-treatment)

    Reporting group title
    Alpelisib + fulvestrant (on-treatment)
    Reporting group description
    		 AEs collected during on-treatment period (up to 30 days post-treatment)

    Serious adverse events
    		 Placebo + fulvestrant (on-treatment) Alpelisib + fulvestrant (on-treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 287 (18.82%)
    110 / 284 (38.73%)
         number of deaths (all causes)
    12
    9
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Second primary malignancy
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 287 (0.00%)
    4 / 284 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 287 (0.00%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 287 (0.00%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (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
    4 / 287 (1.39%)
    4 / 284 (1.41%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (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
    5 / 287 (1.74%)
    4 / 284 (1.41%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 287 (1.05%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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
    Femur fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriospasm coronary
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus tachycardia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (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 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    6 / 284 (2.11%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 287 (0.70%)
    6 / 284 (2.11%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (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
    0 / 287 (0.00%)
    9 / 284 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallstone ileus
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 287 (0.70%)
    5 / 284 (1.76%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 287 (0.00%)
    4 / 284 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 287 (1.05%)
    5 / 284 (1.76%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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
    Dermatitis acneiform
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 287 (0.00%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 287 (0.00%)
    5 / 284 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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 / 287 (0.00%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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 / 287 (0.35%)
    6 / 284 (2.11%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         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
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 287 (1.39%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 287 (0.70%)
    9 / 284 (3.17%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 287 (2.09%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 287 (0.70%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 284 (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
    3 / 287 (1.05%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 287 (0.00%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 287 (1.05%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    28 / 284 (9.86%)
         occurrences causally related to treatment / all
    0 / 0
    30 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 287 (0.35%)
    3 / 284 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 284 (0.35%)
         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 (on-treatment) Alpelisib + fulvestrant (on-treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    244 / 287 (85.02%)
    280 / 284 (98.59%)
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    6 / 287 (2.09%)
    17 / 284 (5.99%)
         occurrences all number
    6
    19
    Hypertension
         subjects affected / exposed
    15 / 287 (5.23%)
    29 / 284 (10.21%)
         occurrences all number
    18
    34
    Hot flush
         subjects affected / exposed
    19 / 287 (6.62%)
    9 / 284 (3.17%)
         occurrences all number
    19
    10
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    14 / 287 (4.88%)
    46 / 284 (16.20%)
         occurrences all number
    20
    60
    Mucosal inflammation
         subjects affected / exposed
    4 / 287 (1.39%)
    53 / 284 (18.66%)
         occurrences all number
    4
    73
    Fatigue
         subjects affected / exposed
    51 / 287 (17.77%)
    73 / 284 (25.70%)
         occurrences all number
    58
    87
    Asthenia
         subjects affected / exposed
    40 / 287 (13.94%)
    64 / 284 (22.54%)
         occurrences all number
    51
    89
    Pyrexia
         subjects affected / exposed
    16 / 287 (5.57%)
    47 / 284 (16.55%)
         occurrences all number
    17
    73
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    32 / 287 (11.15%)
    27 / 284 (9.51%)
         occurrences all number
    36
    33
    Cough
         subjects affected / exposed
    28 / 287 (9.76%)
    36 / 284 (12.68%)
         occurrences all number
    34
    40
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 287 (4.18%)
    22 / 284 (7.75%)
         occurrences all number
    12
    25
    Investigations
    Lipase increased
         subjects affected / exposed
    12 / 287 (4.18%)
    21 / 284 (7.39%)
         occurrences all number
    21
    29
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    23 / 287 (8.01%)
    28 / 284 (9.86%)
         occurrences all number
    24
    33
    Blood creatinine increased
         subjects affected / exposed
    4 / 287 (1.39%)
    36 / 284 (12.68%)
         occurrences all number
    4
    45
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 287 (6.27%)
    32 / 284 (11.27%)
         occurrences all number
    20
    39
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 287 (6.27%)
    28 / 284 (9.86%)
         occurrences all number
    20
    33
    Weight decreased
         subjects affected / exposed
    7 / 287 (2.44%)
    79 / 284 (27.82%)
         occurrences all number
    7
    91
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 287 (13.24%)
    53 / 284 (18.66%)
         occurrences all number
    57
    76
    Dysgeusia
         subjects affected / exposed
    8 / 287 (2.79%)
    39 / 284 (13.73%)
         occurrences all number
    9
    46
    Dizziness
         subjects affected / exposed
    20 / 287 (6.97%)
    27 / 284 (9.51%)
         occurrences all number
    21
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 287 (6.97%)
    29 / 284 (10.21%)
         occurrences all number
    23
    45
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 287 (0.70%)
    15 / 284 (5.28%)
         occurrences all number
    2
    15
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    17 / 287 (5.92%)
    32 / 284 (11.27%)
         occurrences all number
    19
    37
    Dry mouth
         subjects affected / exposed
    13 / 287 (4.53%)
    30 / 284 (10.56%)
         occurrences all number
    17
    33
    Abdominal pain
         subjects affected / exposed
    20 / 287 (6.97%)
    33 / 284 (11.62%)
         occurrences all number
    22
    49
    Abdominal pain upper
         subjects affected / exposed
    13 / 287 (4.53%)
    19 / 284 (6.69%)
         occurrences all number
    15
    23
    Constipation
         subjects affected / exposed
    37 / 287 (12.89%)
    25 / 284 (8.80%)
         occurrences all number
    48
    30
    Diarrhoea
         subjects affected / exposed
    48 / 287 (16.72%)
    167 / 284 (58.80%)
         occurrences all number
    72
    376
    Nausea
         subjects affected / exposed
    64 / 287 (22.30%)
    133 / 284 (46.83%)
         occurrences all number
    82
    203
    Vomiting
         subjects affected / exposed
    27 / 287 (9.41%)
    80 / 284 (28.17%)
         occurrences all number
    36
    126
    Stomatitis
         subjects affected / exposed
    20 / 287 (6.97%)
    70 / 284 (24.65%)
         occurrences all number
    27
    96
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    4 / 287 (1.39%)
    39 / 284 (13.73%)
         occurrences all number
    5
    49
    Rash
         subjects affected / exposed
    20 / 287 (6.97%)
    101 / 284 (35.56%)
         occurrences all number
    23
    143
    Pruritus
         subjects affected / exposed
    19 / 287 (6.62%)
    54 / 284 (19.01%)
         occurrences all number
    22
    71
    Erythema
         subjects affected / exposed
    2 / 287 (0.70%)
    19 / 284 (6.69%)
         occurrences all number
    2
    20
    Dry skin
         subjects affected / exposed
    10 / 287 (3.48%)
    44 / 284 (15.49%)
         occurrences all number
    11
    50
    Alopecia
         subjects affected / exposed
    7 / 287 (2.44%)
    58 / 284 (20.42%)
         occurrences all number
    8
    60
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    24 / 287 (8.36%)
    29 / 284 (10.21%)
         occurrences all number
    25
    32
    Osteonecrosis of jaw
         subjects affected / exposed
    3 / 287 (1.05%)
    15 / 284 (5.28%)
         occurrences all number
    4
    18
    Myalgia
         subjects affected / exposed
    9 / 287 (3.14%)
    20 / 284 (7.04%)
         occurrences all number
    10
    23
    Muscle spasms
         subjects affected / exposed
    12 / 287 (4.18%)
    23 / 284 (8.10%)
         occurrences all number
    12
    28
    Bone pain
         subjects affected / exposed
    19 / 287 (6.62%)
    14 / 284 (4.93%)
         occurrences all number
    21
    14
    Back pain
         subjects affected / exposed
    43 / 287 (14.98%)
    44 / 284 (15.49%)
         occurrences all number
    48
    53
    Arthralgia
         subjects affected / exposed
    56 / 287 (19.51%)
    44 / 284 (15.49%)
         occurrences all number
    87
    51
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 287 (4.53%)
    28 / 284 (9.86%)
         occurrences all number
    27
    49
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 287 (6.62%)
    15 / 284 (5.28%)
         occurrences all number
    22
    27
    Nasopharyngitis
         subjects affected / exposed
    26 / 287 (9.06%)
    24 / 284 (8.45%)
         occurrences all number
    39
    35
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    5 / 287 (1.74%)
    25 / 284 (8.80%)
         occurrences all number
    7
    31
    Decreased appetite
         subjects affected / exposed
    30 / 287 (10.45%)
    103 / 284 (36.27%)
         occurrences all number
    31
    125
    Hyperglycaemia
         subjects affected / exposed
    27 / 287 (9.41%)
    182 / 284 (64.08%)
         occurrences all number
    44
    429

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2016
    The main purpose of this protocol amendment was to modify the study design for the PIK3CA non-mutant cohort from pivotal to a proof-of-concept. The PIK3CA mutant cohort remained unchanged. Consequently the primary and key secondary objectives of the study were to compare the two treatment groups, based on PFS and OS respectively, for patients in the PIK3CA mutant cohort. Comparison of PFS and OS for patients in the PIK3CA non-mutant cohort was part of the secondary objectives
    30 Aug 2016
    The purpose of this amendment was to: - Modify the patient population to be enrolled in the study. Patients who relapsed more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease will no longer be enrolled in the study - Modify the criteria to define futility at the interim analysis in the PIK3CA mutant cohort - Update inclusion criteria and provide more detailed treatment guidance for AE of hyperglycemia and update on AE management for skin toxicity following an advisory-board meeting recommendation - Update the general administration guidelines for alpelisib/placebo based on a food effect and ARA DDI study: alpelisib must be taken with a meal regardless of composition or overall calorie intake. A staggered approach for co-administration of alpelisib with acid reducing agents is no longer required - Change the approach for Blinded Independent Review Committee (BIRC) assessment of PFS from a full read to an audit (sample) based approach. As PFS in the PIK3CA nonmutant cohort is a secondary endpoint, no BIRC assessment will be made for these patients. - Add PFS2 as an exploratory endpoint, defined as the time from randomization to progression on next-line therapy or death, whichever occurs first, in order to make an exploratory assessment of long term benefit intermediate to PFS and OS - Update the estimated timing of interim and final PFS and OS analyses taking into account current and expected enrolment rates.
    14 Dec 2016
    The purpose of this amendment was to: - Modify the interim PFS analysis efficacy stopping boundary from Lan-DeMets (O’Brien- Fleming) to Haybittle-Peto boundary in the PIK3CA mutant cohort - Ensure that the Novartis clinical team will remain blinded to the treatment allocation in both cohorts until the time point when PIK3CA mutant cohort can be unblinded. The responsibility for performing the final PFS analysis (and first interim OS analysis) in the PIK3CA non-mutant cohort is modified from the Novartis Clinical Team to an independent statistical group. The results from this analysis will be provided by the independent statistical group to the DMC for decision making on the outcome of the PIK3CA non-mutant cohort
    22 Nov 2017
    The purpose of this amendment was to provide updated guidance on the management of skin and subcutaneous reactions.
    11 Feb 2020
    The purpose of this amendment was to provide a protocol update on the following based on the released IB Edition 13: -Update on permitted concomitant medications and the use of bisphosphonates/denosumab -Update on guidance of dose interruption/modifications, management of AEs associated with the use of alpelisib, and guidance for follow-up on toxicities -Add AST/ALT/Total Bilirubin dose modifications in Table 6-3 (based on a feedback from FDA to match PIQRAY USPI). Accordingly, Table 6-4 was replaced with a table on alternative causes of liver diseases; and section on follow-up of potential drug-induced liver injury (DILI) was updated -Minor update for the guidelines of skin rash (based on feedback from KOL Dermatologist) -Add DRESS as one of possible manifestations of severe cutaneous skin reactions -Update of the VES for PRO, ECG, ECHO/MUGA assessments

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 9999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/ for complete trial results
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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