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    Clinical Trial Results:
    A randomized double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment

    Summary
    EudraCT number
    2015-000617-43
    Trial protocol
    SE   DE   AT   ES   CZ   DK   NL   HU   BE   BG   FR   PT   IT  
    Global end of trial date
    11 Jan 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Nov 2023
    First version publication date
    18 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLEE011F2301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02422615
    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
    11 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare progression free survival (PFS) between ribociclib in combination with fulvestrant to placebo in combination with fulvestrant among men and postmenopausal women with HR+, HER2-negative advanced breast cancer who received no or only one prior endocrine treatment for advanced disease.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from theDeclaration of Helsinki and the International Conference onHarmonization (ICH) Good Clinical Practice (GCP) guidelines. All the localregulatory requirements pertinent to safety of trial subjects were alsofollowed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Jun 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
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 56
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Canada: 41
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Czechia: 21
    Country: Number of subjects enrolled
    Denmark: 32
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Germany: 108
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Jordan: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Lebanon: 6
    Country: Number of subjects enrolled
    Malaysia: 6
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Netherlands: 56
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Spain: 56
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Norway: 5
    Worldwide total number of subjects
    726
    EEA total number of subjects
    476
    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)
    387
    From 65 to 84 years
    335
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    174 sites across 30 countries enrolled participants

    Pre-assignment
    Screening details
    Screening assessments were conducted up to 28 days prior to the randomization

    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
    Blinding implementation details
    A protocol amendment 4 (dated 29-Jan-2020) allowed for unblinding of study participants, and those still receiving placebo had the option to switch to the ribociclib arm. The decision for crossover was made at the investigator’s discretion and required patient consent.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ribociclib + fulvestrant
    Arm description
    Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    LEE011
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib capsules were administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules were administered orally for 21 consecutive days within a 28-day cycle.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant was administered via intramuscular injections at a dose of 500mg every 28 days, starting on Day 1 of each cycle. In Cycle 1, an additional dose of Fulvestrant was given on Day 15

    Arm title
    Placebo + fulvestrant
    Arm description
    Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.
    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
    Fulvestrant was administered via intramuscular injections at a dose of 500mg every 28 days, starting on Day 1 of each cycle. In Cycle 1, an additional dose of Fulvestrant was given on Day 15

    Number of subjects in period 1
    Ribociclib + fulvestrant Placebo + fulvestrant
    Started
    484
    242
    Untreated
    1
    1
    Crossover cohort
    0
    3
    Completed
    0
    0
    Not completed
    484
    242
         Adverse event, serious fatal
    2
    1
         Physician decision
    32
    8
         Adverse event, non-fatal
    51
    9
         Technical problems
    -
    1
         Protocol deviation
    1
    1
         Study terminated per protocol
    46
    14
         Progressive disease
    314
    200
         Subject/guardian decision
    38
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ribociclib + fulvestrant
    Reporting group description
    Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1.

    Reporting group title
    Placebo + fulvestrant
    Reporting group description
    Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.

    Reporting group values
    Ribociclib + fulvestrant Placebo + fulvestrant Total
    Number of subjects
    484 242 726
    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)
    258 129 387
        From 65-84 years
    223 112 335
        85 years and over
    3 1 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    63.4 ± 9.78 62.8 ± 10.59 -
    Sex: Female, Male
    Units: Participants
        Female
    484 242 726
        Male
    0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    406 213 619
        Asian
    45 18 63
        Native American
    5 1 6
        Black
    3 2 5
        Other
    10 3 13
        Unkown
    15 5 20

    End points

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    End points reporting groups
    Reporting group title
    Ribociclib + fulvestrant
    Reporting group description
    Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1.

    Reporting group title
    Placebo + fulvestrant
    Reporting group description
    Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant.

    Primary: Progression Free Survival (PFS) per Investigator assessment

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    End point title
    Progression Free Survival (PFS) per Investigator assessment
    End point description
    PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via local radiology assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. The distribution of PFS between the two arms was compared using a stratified log-rank test at a one-sided 2.5% level of significance. The PFS hazard ratio with two-sided 95% confidence interval was derived from the stratified Cox proportional hazards model.
    End point type
    Primary
    End point timeframe
    From randomization to first documented progression or death, assessed up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Months
        median (confidence interval 95%)
    20.5 (18.5 to 23.5)
    12.8 (10.9 to 16.3)
    Statistical analysis title
    PFS: Ribociclib vs placebo
    Comparison groups
    Ribociclib + fulvestrant v Placebo + fulvestrant
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0 [1]
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.593
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    0.732
    Notes
    [1] - P-value= 0.00000041

    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 participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per investigator assessment. CR: Disappearance of all lesions with lymph nodes measuring < 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 approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Percentage of participants
        number (confidence interval 95%)
    32.4 (28.3 to 36.6)
    21.5 (16.3 to 26.7)
    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
    CBR was defined as the percentage of participants with a best overall response of CR or PR or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1 as per investigator assessment. CR: Disappearance of all lesions with lymph nodes measuring < 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 approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Percentage of participants
        number (confidence interval 95%)
    70.2 (66.2 to 74.3)
    62.8 (56.7 to 68.9)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) per Blinded Independent Review Committee (BIRC)

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    End point title
    Progression Free Survival (PFS) per Blinded Independent Review Committee (BIRC)
    End point description
    PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via BIRC assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From randomization to first documented progression or death, assessed up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Months
        median (confidence interval 95%)
    9999 (18.2 to 9999)
    10.9 (3.8 to 17.2)
    Statistical analysis title
    PFS: Ribociclib vs Placebo
    Comparison groups
    Ribociclib + fulvestrant v Placebo + fulvestrant
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.492
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.345
         upper limit
    0.703

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status. OS was estimated using the Kaplan-Meier method. The median OS, along with 95% confidence intervals (CIs), was reported for each treatment group. The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From randomization to death, assessed up to approximately 46 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Months
        median (confidence interval 95%)
    9999 (42.5 to 9999)
    40.0 (37.0 to 9999)
    Statistical analysis title
    OS: Ribociclib vs Placebo
    Comparison groups
    Ribociclib + fulvestrant v Placebo + fulvestrant
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.00455
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.724
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.568
         upper limit
    0.924

    Secondary: Time to definitive 10% deterioration in the global health status/quality of life (GHS/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 definitive 10% deterioration in the global health status/quality of life (GHS/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, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range between 0 and 100. A high score for GHS/QoL represents better functioning or QoL. The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Months
        median (confidence interval 95%)
    9999 (22.1 to 9999)
    19.4 (16.6 to 9999)
    No statistical analyses for this end point

    Secondary: Time to definitive deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in one score category

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    End point title
    Time to definitive deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) in one score category
    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 was the time from randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from baseline or death. A deterioration was considered definitive if no improvements were observed at a subsequent time. The KM method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. 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. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Months
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) per investigator assessment

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    End point title
    Duration of response (DOR) per investigator assessment
    End point description
    DOR was defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate DOR, and the median DOR, along with 95% confidence intervals, was reported for each treatment group. If a participant had not had an event, duration was censored at the date of last adequate tumor assessment. CR: Disappearance of all lesions with lymph nodes measuring < 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. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From first documented response to progression or death, assessed up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    157
    52
    Units: Months
        median (confidence interval 95%)
    9999 (16.1 to 9999)
    9999 (13.8 to 9999)
    No statistical analyses for this end point

    Secondary: Time to response (TTR) per investigator assessment

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    End point title
    Time to response (TTR) per investigator assessment
    End point description
    TTR was defined as the time from randomization to the first documented and confirmed response (CR or PR) as defined by RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate TTR, and the median TTR, along with 95% confidence intervals, was reported for each treatment group. Participants who did not achieve a confirmed response were censored at the maximum follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise. CR: Disappearance of all lesions with lymph nodes measuring < 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. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    From randomization to first response, assessed up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Months
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    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, a GHS/QoL scale, and 6 single items. GHS/QoL scale scores range 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 indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits occurred every 8 weeks during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Baseline, every 8 weeks after randomization during 18 months, then every 12 weeks up to end of treatment; end of treatment; and every 8 or 12 weeks post-treatment until progression (post-treatment efficacy visits), assessed up to approximately 26 months
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    361
    169
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Cycle 3 Day 1 (n=361/169)
    4.5 ± 18.53
    2.7 ± 17.50
        Cycle 5 Day 1 (n=316/149)
    4.2 ± 19.97
    3.2 ± 18.09
        Cycle 7 Day 1 (n=300/133)
    4.9 ± 19.47
    4.3 ± 17.30
        Cycle 9 Day 1 (n=283/133)
    4.1 ± 19.36
    3.3 ± 17.61
        Cycle 11 Day 1 (n=251/116)
    4.9 ± 17.57
    2.3 ± 18.21
        Cycle 13 Day 1 (n=240/105)
    4.4 ± 18.53
    1.3 ± 19.48
        Cycle 15 Day 1 (n=218/96)
    3.6 ± 18.34
    3.6 ± 19.86
        Cycle 17 Day 1 (n=216/84)
    3.9 ± 20.31
    3.4 ± 21.61
        Cycle 19 Day 1 (n=185/82)
    3.8 ± 17.57
    3.7 ± 18.52
        Cycle 22 Day 1 (n=118/46)
    6.6 ± 20.78
    4.7 ± 17.00
        Cycle 25 Day 1 (n=54/19)
    5.7 ± 16.81
    8.3 ± 18.22
        Cycle 28 Day 1 (n=12/3)
    12.5 ± 16.48
    19.4 ± 12.73
        End of treatment (EOT) (n=184/113)
    -5.2 ± 25.84
    -5.5 ± 24.54
        Post EOT1 (n=11/2)
    4.5 ± 21.20
    -33.3 ± 23.57
        Post EOT2 (n=7/2)
    -4.8 ± 19.75
    -16.7 ± 23.57
        Post EOT3 (n=4/2)
    14.6 ± 24.88
    -16.7 ± 0.00
        Post EOT4 (n=5/1)
    10.0 ± 20.75
    -25.0 ± 9999
        Post EOT5 (n=3/0)
    13.9 ± 20.97
    9999 ± 9999
        Post EOT6 (n=3/0)
    22.2 ± 12.73
    9999 ± 9999
        Post EOT7 (n=3/0)
    19.4 ± 20.97
    9999 ± 9999
        Post EOT8 (n=2/0)
    37.5 ± 17.68
    9999 ± 9999
        Post EOT9 (n=3/0)
    8.3 ± 46.40
    9999 ± 9999
        Post EOT10 (n=1/0)
    -8.3 ± 9999
    9999 ± 9999
    No statistical analyses for this end point

    Secondary: Ribociclib plasma concentrations

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    End point title
    Ribociclib plasma concentrations [2]
    End point description
    Blood samples were collected to assess the concentration by time point for ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption. Note: 9999 indicates that the value was not estimable
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1 and Cycle 2 at Day (D) 15 pre-dose and at 2, 4, and 6 hours (h) post-dose. 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: This endpoint reports results for the arm that received ribociclib
    End point values
    Ribociclib + fulvestrant
    Number of subjects analysed
    253
    Units: nanogram (ng) / miliLiter (mL)
    geometric mean (geometric coefficient of variation)
        C1D15 predose (ribociclib 600 mg) n=253
    627 ± 67.6
        C1D15 predose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 predose (ribociclib 200 mg) n=0
    9999 ± 9999
        C1D15 2 hours post-dose (ribociclib 600 mg) n=102
    1670 ± 52.0
        C1D15 2 hours post-dose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 2 hours post-dose (ribociclib 200 mg) n=0
    9999 ± 9999
        C1D15 4 hours post-dose (ribociclib 600 mg) n=107
    1690 ± 46.2
        C1D15 4 hours post-dose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 4 hours post-dose (ribociclib 200 mg) n=0
    9999 ± 9999
        C1D15 6 hours post-dose (ribociclib 600 mg) n=107
    1420 ± 50.9
        C1D15 6 hours post-dose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 6 hours post-dose (ribociclib 200 mg) n=0
    9999 ± 9999
        C2D15 predose (ribociclib 600 mg) n=177
    553 ± 80.7
        C2D15 predose (ribociclib 400 mg) n=7
    220 ± 81.6
        C2D15 predose (ribociclib 200 mg) n=0
    9999 ± 9999
        C2D15 2 hours post-dose (ribociclib 600 mg) n=75
    1470 ± 80.7
        C2D15 2 hours post-dose (ribociclib 400 mg) n=7
    794 ± 85.0
        C2D15 2 hours post-dose (ribociclib 200 mg) n=1
    104 ± 9999
        C2D15 4 hours post-dose (ribociclib 600 mg) n=79
    1610 ± 53.6
        C2D15 4 hours post-dose (ribociclib 400 mg) n=7
    913 ± 69.4
        C2D15 4 hours post-dose (ribociclib 200 mg) n=1
    112 ± 9999
        C2D15 6 hours post-dose (ribociclib 600 mg) n=69
    1280 ± 89.6
        C2D15 6 hours post-dose (ribociclib 400 mg) n=5
    710 ± 47.4
        C2D15 6 hours post-dose (ribociclib 200 mg) n=1
    104 ± 9999
    No statistical analyses for this end point

    Secondary: LEQ803 plasma concentrations

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    End point title
    LEQ803 plasma concentrations [3]
    End point description
    Blood samples were collected to assess the concentration by time point for LEQ803, a metabolite of ribociclib. Participants were classified into the following dose groups at each timepoint: 1) ribociclib 600 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 600 mg immediately prior to the blood collection without a dose change or interruption. 2) ribociclib 400 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 400 mg immediately prior to the blood collection without a dose change or interruption. 3) ribociclib 200 mg: consisted of all participants who provided evaluable concentrations after receiving at least 10 consecutive daily ribociclib doses of 200 mg immediately prior to the blood collection without a dose change or interruption.
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1 and Cycle 2 at Day (D) 15 pre-dose and at 2, 4, and 6 hours (h) post-dose. Cycle = 28 days
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint reports results for the arm that received ribociclib
    End point values
    Ribociclib + fulvestrant
    Number of subjects analysed
    253
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        C1D15 predose (ribociclib 600 mg) n=253
    75.6 ± 50.4
        C1D15 predose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 predose (ribociclib 200 mg) n=0
    9999 ± 9999
        C1D15 2 hours post-dose (ribociclib 600 mg) n=102
    134 ± 44.5
        C1D15 2 hours post-dose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 2 hours post-dose (ribociclib 200 mg) n=0
    9999 ± 9999
        C1D15 4 hours post-dose (ribociclib 600 mg) n=107
    137 ± 42.0
        C1D15 4 hours post-dose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 4 hours post-dose (ribociclib 200 mg) n=0
    9999 ± 9999
        C1D15 6 hours post-dose (ribociclib 600 mg) n=92
    128 ± 42.4
        C1D15 6 hours post-dose (ribociclib 400 mg) n=0
    9999 ± 9999
        C1D15 6 hours post-dose (ribociclib 200 mg) n=0
    9999 ± 9999
        C2D15 predose (ribociclib 600 mg) n=177
    72.7 ± 62.9
        C2D15 predose (ribociclib 400 mg) n=7
    46.2 ± 52.3
        C2D15 predose (ribociclib 200 mg) n=0
    9999 ± 9999
        C2D15 2 hours post-dose (ribociclib 600 mg) n=75
    126 ± 56.4
        C2D15 2 hours post-dose (ribociclib 400 mg) n=7
    70.8 ± 68.5
        C2D15 2 hours post-dose (ribociclib 200 mg) n=1
    36.0 ± 9999
        C2D15 4 hours post-dose (ribociclib 600 mg) n=79
    134 ± 44.9
        C2D15 4 hours post-dose (ribociclib 400 mg) n=7
    79.3 ± 67.2
        C2D15 4 hours post-dose (ribociclib 200 mg) n=1
    41.9 ± 9999
        C2D15 6 hours post-dose (ribociclib 600 mg) n=69
    122 ± 60.1
        C2D15 6 hours post-dose (ribociclib 400 mg) n=5
    72.3 ± 75.4
        C2D15 6 hours post-dose (ribociclib 200 mg) n=1
    38.3 ± 9999
    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 treatment or one day before first administration of crossover treatment (for crossover participants), whichever came first Crossover on-treatment deaths were collected from start of crossover treatment up to 30 days after last dose of crossover treatment. Post-treatment efficacy/survival follow-up deaths were collected from day 31 after last dose of study treatment to end of study. Crossover post-treatment efficacy/survival follow-up deaths were collected from day 31 after last dose of crossover treatment to end of study.
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment: Up to 28 days. On-treatment: Up to 82 months. Crossover on-treatment: Up to 3.5 months. Post-treatment efficacy/survival follow-up: Up to 82 months. Crossover post-treatment efficacy/survival follow-up: Up to 1 year
    End point values
    Ribociclib + fulvestrant Placebo + fulvestrant
    Number of subjects analysed
    484
    242
    Units: Participants
        Pre-treatment deaths
    0
    0
        On-treatment deaths
    13
    8
        Crossover on-treatment deaths
    0
    0
        Post-treatment efficacy/survival deaths
    264
    153
        Crossover post-treatment efficacy/survival deaths
    0
    1
        All deaths
    277
    162
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Ribociclib + Fulvestrant
    Reporting group description
    Ribociclib + Fulvestrant

    Reporting group title
    Placebo+Fulvestrant crossover to Ribociclib+Fulvestrant
    Reporting group description
    Placebo+Fulvestrant crossover to Ribociclib+Fulvestrant

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    Placebo + Fulvestrant

    Serious adverse events
    Ribociclib + Fulvestrant Placebo+Fulvestrant crossover to Ribociclib+Fulvestrant Placebo + Fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    179 / 483 (37.06%)
    1 / 3 (33.33%)
    51 / 241 (21.16%)
         number of deaths (all causes)
    13
    0
    8
         number of deaths resulting from adverse events
    2
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Terminal state
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 483 (1.24%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haematoma
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    9 / 483 (1.86%)
    0 / 3 (0.00%)
    5 / 241 (2.07%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    7 / 483 (1.45%)
    0 / 3 (0.00%)
    3 / 241 (1.24%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 483 (1.04%)
    0 / 3 (0.00%)
    3 / 241 (1.24%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    5 / 483 (1.04%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    5 / 483 (1.04%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve sclerosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    7 / 483 (1.45%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    7 / 483 (1.45%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 483 (1.24%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Myopia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    6 / 483 (1.24%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal incontinence
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aphthous ulcer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gingival disorder
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    10 / 483 (2.07%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    7 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    8 / 483 (1.66%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    4 / 8
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    Biliary colic
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 483 (1.24%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder hypertrophy
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle twitching
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 483 (2.69%)
    0 / 3 (0.00%)
    3 / 241 (1.24%)
         occurrences causally related to treatment / all
    2 / 13
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 483 (0.83%)
    1 / 3 (33.33%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 483 (0.83%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 483 (0.41%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    3 / 483 (0.62%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 483 (0.21%)
    0 / 3 (0.00%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 483 (0.00%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ribociclib + Fulvestrant Placebo+Fulvestrant crossover to Ribociclib+Fulvestrant Placebo + Fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    475 / 483 (98.34%)
    3 / 3 (100.00%)
    225 / 241 (93.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    66 / 483 (13.66%)
    0 / 3 (0.00%)
    26 / 241 (10.79%)
         occurrences all number
    88
    0
    29
    Hypotension
         subjects affected / exposed
    18 / 483 (3.73%)
    1 / 3 (33.33%)
    6 / 241 (2.49%)
         occurrences all number
    22
    1
    6
    Hot flush
         subjects affected / exposed
    69 / 483 (14.29%)
    0 / 3 (0.00%)
    40 / 241 (16.60%)
         occurrences all number
    77
    0
    47
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    74 / 483 (15.32%)
    0 / 3 (0.00%)
    31 / 241 (12.86%)
         occurrences all number
    114
    0
    38
    Fatigue
         subjects affected / exposed
    164 / 483 (33.95%)
    0 / 3 (0.00%)
    82 / 241 (34.02%)
         occurrences all number
    218
    0
    102
    Influenza like illness
         subjects affected / exposed
    38 / 483 (7.87%)
    0 / 3 (0.00%)
    17 / 241 (7.05%)
         occurrences all number
    49
    0
    18
    Injection site pain
         subjects affected / exposed
    25 / 483 (5.18%)
    0 / 3 (0.00%)
    14 / 241 (5.81%)
         occurrences all number
    30
    0
    16
    Non-cardiac chest pain
         subjects affected / exposed
    25 / 483 (5.18%)
    0 / 3 (0.00%)
    13 / 241 (5.39%)
         occurrences all number
    31
    0
    13
    Oedema peripheral
         subjects affected / exposed
    70 / 483 (14.49%)
    0 / 3 (0.00%)
    16 / 241 (6.64%)
         occurrences all number
    95
    0
    20
    Pyrexia
         subjects affected / exposed
    70 / 483 (14.49%)
    0 / 3 (0.00%)
    17 / 241 (7.05%)
         occurrences all number
    102
    0
    22
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    7 / 483 (1.45%)
    0 / 3 (0.00%)
    14 / 241 (5.81%)
         occurrences all number
    7
    0
    15
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    39 / 483 (8.07%)
    0 / 3 (0.00%)
    17 / 241 (7.05%)
         occurrences all number
    48
    0
    20
    Dyspnoea
         subjects affected / exposed
    85 / 483 (17.60%)
    0 / 3 (0.00%)
    32 / 241 (13.28%)
         occurrences all number
    118
    0
    42
    Cough
         subjects affected / exposed
    126 / 483 (26.09%)
    0 / 3 (0.00%)
    42 / 241 (17.43%)
         occurrences all number
    188
    0
    51
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    63 / 483 (13.04%)
    1 / 3 (33.33%)
    30 / 241 (12.45%)
         occurrences all number
    70
    1
    34
    Depression
         subjects affected / exposed
    38 / 483 (7.87%)
    0 / 3 (0.00%)
    13 / 241 (5.39%)
         occurrences all number
    40
    0
    14
    Anxiety
         subjects affected / exposed
    34 / 483 (7.04%)
    0 / 3 (0.00%)
    15 / 241 (6.22%)
         occurrences all number
    36
    0
    16
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    77 / 483 (15.94%)
    0 / 3 (0.00%)
    16 / 241 (6.64%)
         occurrences all number
    94
    0
    26
    Amylase increased
         subjects affected / exposed
    13 / 483 (2.69%)
    1 / 3 (33.33%)
    3 / 241 (1.24%)
         occurrences all number
    27
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    70 / 483 (14.49%)
    0 / 3 (0.00%)
    17 / 241 (7.05%)
         occurrences all number
    91
    0
    26
    Blood cholesterol increased
         subjects affected / exposed
    21 / 483 (4.35%)
    0 / 3 (0.00%)
    14 / 241 (5.81%)
         occurrences all number
    22
    0
    17
    Blood creatinine increased
         subjects affected / exposed
    44 / 483 (9.11%)
    1 / 3 (33.33%)
    10 / 241 (4.15%)
         occurrences all number
    75
    1
    20
    Electrocardiogram QT prolonged
         subjects affected / exposed
    30 / 483 (6.21%)
    0 / 3 (0.00%)
    3 / 241 (1.24%)
         occurrences all number
    72
    0
    19
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    39 / 483 (8.07%)
    0 / 3 (0.00%)
    19 / 241 (7.88%)
         occurrences all number
    48
    0
    28
    Lipase increased
         subjects affected / exposed
    24 / 483 (4.97%)
    0 / 3 (0.00%)
    14 / 241 (5.81%)
         occurrences all number
    51
    0
    28
    Neutrophil count decreased
         subjects affected / exposed
    105 / 483 (21.74%)
    0 / 3 (0.00%)
    4 / 241 (1.66%)
         occurrences all number
    458
    0
    21
    Weight decreased
         subjects affected / exposed
    27 / 483 (5.59%)
    0 / 3 (0.00%)
    12 / 241 (4.98%)
         occurrences all number
    30
    0
    12
    White blood cell count decreased
         subjects affected / exposed
    66 / 483 (13.66%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences all number
    148
    0
    12
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    19 / 483 (3.93%)
    0 / 3 (0.00%)
    16 / 241 (6.64%)
         occurrences all number
    21
    0
    19
    Headache
         subjects affected / exposed
    120 / 483 (24.84%)
    0 / 3 (0.00%)
    51 / 241 (21.16%)
         occurrences all number
    184
    0
    87
    Dizziness
         subjects affected / exposed
    71 / 483 (14.70%)
    1 / 3 (33.33%)
    22 / 241 (9.13%)
         occurrences all number
    99
    1
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    92 / 483 (19.05%)
    2 / 3 (66.67%)
    21 / 241 (8.71%)
         occurrences all number
    188
    2
    31
    Lymphopenia
         subjects affected / exposed
    31 / 483 (6.42%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences all number
    46
    0
    2
    Neutropenia
         subjects affected / exposed
    279 / 483 (57.76%)
    1 / 3 (33.33%)
    6 / 241 (2.49%)
         occurrences all number
    1240
    1
    10
    Thrombocytopenia
         subjects affected / exposed
    30 / 483 (6.21%)
    0 / 3 (0.00%)
    5 / 241 (2.07%)
         occurrences all number
    63
    0
    8
    Leukopenia
         subjects affected / exposed
    93 / 483 (19.25%)
    0 / 3 (0.00%)
    1 / 241 (0.41%)
         occurrences all number
    200
    0
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    35 / 483 (7.25%)
    0 / 3 (0.00%)
    4 / 241 (1.66%)
         occurrences all number
    39
    0
    4
    Eye disorders
    Dry eye
         subjects affected / exposed
    28 / 483 (5.80%)
    0 / 3 (0.00%)
    8 / 241 (3.32%)
         occurrences all number
    30
    0
    8
    Lacrimation increased
         subjects affected / exposed
    27 / 483 (5.59%)
    0 / 3 (0.00%)
    2 / 241 (0.83%)
         occurrences all number
    31
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    46 / 483 (9.52%)
    0 / 3 (0.00%)
    18 / 241 (7.47%)
         occurrences all number
    56
    0
    23
    Abdominal pain upper
         subjects affected / exposed
    59 / 483 (12.22%)
    0 / 3 (0.00%)
    19 / 241 (7.88%)
         occurrences all number
    73
    0
    20
    Colitis
         subjects affected / exposed
    3 / 483 (0.62%)
    1 / 3 (33.33%)
    1 / 241 (0.41%)
         occurrences all number
    3
    1
    1
    Constipation
         subjects affected / exposed
    123 / 483 (25.47%)
    0 / 3 (0.00%)
    33 / 241 (13.69%)
         occurrences all number
    161
    0
    42
    Diarrhoea
         subjects affected / exposed
    164 / 483 (33.95%)
    1 / 3 (33.33%)
    54 / 241 (22.41%)
         occurrences all number
    300
    3
    85
    Dry mouth
         subjects affected / exposed
    27 / 483 (5.59%)
    0 / 3 (0.00%)
    5 / 241 (2.07%)
         occurrences all number
    28
    0
    5
    Dyspepsia
         subjects affected / exposed
    56 / 483 (11.59%)
    0 / 3 (0.00%)
    15 / 241 (6.22%)
         occurrences all number
    70
    0
    18
    Dysphagia
         subjects affected / exposed
    12 / 483 (2.48%)
    1 / 3 (33.33%)
    3 / 241 (1.24%)
         occurrences all number
    13
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    25 / 483 (5.18%)
    0 / 3 (0.00%)
    5 / 241 (2.07%)
         occurrences all number
    27
    0
    6
    Nausea
         subjects affected / exposed
    226 / 483 (46.79%)
    1 / 3 (33.33%)
    75 / 241 (31.12%)
         occurrences all number
    377
    1
    104
    Stomatitis
         subjects affected / exposed
    63 / 483 (13.04%)
    0 / 3 (0.00%)
    13 / 241 (5.39%)
         occurrences all number
    84
    0
    15
    Toothache
         subjects affected / exposed
    33 / 483 (6.83%)
    0 / 3 (0.00%)
    5 / 241 (2.07%)
         occurrences all number
    44
    0
    5
    Vomiting
         subjects affected / exposed
    135 / 483 (27.95%)
    1 / 3 (33.33%)
    34 / 241 (14.11%)
         occurrences all number
    208
    1
    49
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    106 / 483 (21.95%)
    0 / 3 (0.00%)
    19 / 241 (7.88%)
         occurrences all number
    155
    0
    25
    Pruritus
         subjects affected / exposed
    107 / 483 (22.15%)
    0 / 3 (0.00%)
    18 / 241 (7.47%)
         occurrences all number
    150
    0
    23
    Erythema
         subjects affected / exposed
    26 / 483 (5.38%)
    0 / 3 (0.00%)
    3 / 241 (1.24%)
         occurrences all number
    32
    0
    3
    Dry skin
         subjects affected / exposed
    40 / 483 (8.28%)
    0 / 3 (0.00%)
    8 / 241 (3.32%)
         occurrences all number
    44
    0
    8
    Alopecia
         subjects affected / exposed
    100 / 483 (20.70%)
    0 / 3 (0.00%)
    12 / 241 (4.98%)
         occurrences all number
    107
    0
    13
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 483 (0.83%)
    2 / 3 (66.67%)
    1 / 241 (0.41%)
         occurrences all number
    4
    2
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    86 / 483 (17.81%)
    0 / 3 (0.00%)
    48 / 241 (19.92%)
         occurrences all number
    115
    0
    69
    Neck pain
         subjects affected / exposed
    41 / 483 (8.49%)
    0 / 3 (0.00%)
    14 / 241 (5.81%)
         occurrences all number
    47
    0
    14
    Myalgia
         subjects affected / exposed
    49 / 483 (10.14%)
    0 / 3 (0.00%)
    27 / 241 (11.20%)
         occurrences all number
    64
    0
    30
    Musculoskeletal pain
         subjects affected / exposed
    27 / 483 (5.59%)
    0 / 3 (0.00%)
    16 / 241 (6.64%)
         occurrences all number
    35
    0
    19
    Musculoskeletal chest pain
         subjects affected / exposed
    21 / 483 (4.35%)
    0 / 3 (0.00%)
    23 / 241 (9.54%)
         occurrences all number
    29
    0
    25
    Muscle spasms
         subjects affected / exposed
    37 / 483 (7.66%)
    0 / 3 (0.00%)
    14 / 241 (5.81%)
         occurrences all number
    43
    0
    18
    Arthralgia
         subjects affected / exposed
    155 / 483 (32.09%)
    0 / 3 (0.00%)
    91 / 241 (37.76%)
         occurrences all number
    295
    0
    153
    Back pain
         subjects affected / exposed
    108 / 483 (22.36%)
    0 / 3 (0.00%)
    46 / 241 (19.09%)
         occurrences all number
    154
    0
    64
    Bone pain
         subjects affected / exposed
    49 / 483 (10.14%)
    0 / 3 (0.00%)
    24 / 241 (9.96%)
         occurrences all number
    71
    0
    25
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    34 / 483 (7.04%)
    0 / 3 (0.00%)
    12 / 241 (4.98%)
         occurrences all number
    45
    0
    14
    Cystitis
         subjects affected / exposed
    26 / 483 (5.38%)
    0 / 3 (0.00%)
    9 / 241 (3.73%)
         occurrences all number
    36
    0
    9
    Influenza
         subjects affected / exposed
    31 / 483 (6.42%)
    0 / 3 (0.00%)
    12 / 241 (4.98%)
         occurrences all number
    32
    0
    13
    Nasopharyngitis
         subjects affected / exposed
    70 / 483 (14.49%)
    0 / 3 (0.00%)
    34 / 241 (14.11%)
         occurrences all number
    109
    0
    53
    Oral candidiasis
         subjects affected / exposed
    0 / 483 (0.00%)
    1 / 3 (33.33%)
    0 / 241 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    11 / 483 (2.28%)
    1 / 3 (33.33%)
    4 / 241 (1.66%)
         occurrences all number
    22
    1
    4
    Pharyngitis
         subjects affected / exposed
    10 / 483 (2.07%)
    1 / 3 (33.33%)
    5 / 241 (2.07%)
         occurrences all number
    13
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    60 / 483 (12.42%)
    0 / 3 (0.00%)
    19 / 241 (7.88%)
         occurrences all number
    88
    0
    25
    Urinary tract infection
         subjects affected / exposed
    62 / 483 (12.84%)
    1 / 3 (33.33%)
    29 / 241 (12.03%)
         occurrences all number
    137
    1
    41
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    93 / 483 (19.25%)
    0 / 3 (0.00%)
    32 / 241 (13.28%)
         occurrences all number
    112
    0
    36
    Hyperglycaemia
         subjects affected / exposed
    27 / 483 (5.59%)
    0 / 3 (0.00%)
    11 / 241 (4.56%)
         occurrences all number
    37
    0
    11

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2016
    Guidance for management of QTcF prolongation and hepatic toxicities. As QT prolongation is an important identified risk identified risk in patients treated with ribociclib, ECG monitoring was updated from single ECG monitoring to triplicate ECG monitoring. As hepatic toxicity is an important identified risk in patients treated with ribociclib, liver function monitoring and dose adjustment guidance were updated. Additional blood collections for laboratory assessments to further characterize potential drug-induced liver injury, including immunologic markers (e.g. immunoglobulins, C-reactive protein, autoimmune hepatitis markers) and total bile acids as part of clinical safety assessments, as well as blood collections for retrospective analysis of exploratory liver biomarkers (e.g. micro-RNA 122) and genome wide association studies (GWAS/HLA) were added. Management of dose modifications based on local laboratory results. Modification of the study population and eligibility criteria to include men (based on Health Authority interactions)
    28 Jul 2016
    Originally planned futility interim analysis (IA) was eliminated. Originally planned efficacy IA was eliminated and a requirement for a minimum amount of events coming from 1st line patients in the final analysis was added. PFS based on BIRC assessments was not a secondary endpoint but was added as a supportive analysis for the primary analysis. Progression on next-line therapy was added as an exploratory objective.
    06 Aug 2018
    Updated the dose adjustment and management recommendations for QTcF prolongation. Updated the prohibited concomitant medications based on drug-drug interaction and comedication considerations. PRO assessment schedule updated to follow the efficacy assessment schedule. As the radiology review from the blinded independent review is completed, note added on stopping the transmission of images to Contract Research organization (CRO). Updated the withdrawal of consent language to align with the new Global Data Protection Requirements.
    29 Jan 2020
    Allowed unblinding of all patients and investigators to allow for knowledge of patient’s current treatment allocation and allow for patients currently receiving placebo the opportunity to transition to ribociclib treatment per investigator discretion. Also, visit evaluation schedule was updated for patients on placebo transitioning to ribociclib. Allowed for central safety electrocardiogram (ECG) assessments to cease and ECG assessments to be performed locally. Added guidance that patient reported outcome (PRO) measures should no longer be collected. Updated the biomarker collection schedule. The blood for circulating tumor DNA will be collected from all patients only at end of trial (EOT) and an additional collection on the first day of LEE011 treatment for patients who elect to cross-over from placebo

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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