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    Clinical Trial Results:
    A national phase IIIb, multi-center, open label study for women and men with hormone-receptor positive, HER2-negative locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole RIBECCA RIBociclib for the trEatment of advanCed breast CAncer

    Summary
    EudraCT number
    2016-002556-24
    Trial protocol
    DE  
    Global end of trial date
    06 Feb 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLEE011XDE01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03096847
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Study Director  , Novartis Pharmaceuticals, 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
    06 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was the assessment of the clinical benefit rate (CBR) after 24 weeks for the total population and for cohorts A and B separately: -To assess the CBR after 24 weeks for ribociclib (LEE011) in combination with letrozole among postmenopausal women and men with hormone receptor positive, HER2- negative, advanced breast cancer who received no prior treatment for advanced disease. (70% group) (Cohort A) -To assess the CBR after 24 weeks for ribociclib (LEE011) in combination with letrozole and goserelin among pre-, and perimenopausal women who received no prior treatment for advanced disease as well as pre-, peri- and postmenopausal women and men with hormone receptor positive, HER2- negative, advanced breast cancer who received no more than 1 prior chemotherapy and 2 prior lines of endocrine therapy for advanced disease (30% group) (Cohort B)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 502
    Worldwide total number of subjects
    502
    EEA total number of subjects
    502
    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)
    256
    From 65 to 84 years
    240
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    584 patients were screened and defined as Cohort A, 191 patients defined Cohort B. Cohort B was divided into Cohort B1 comprising 34 pre- or perimenopausal women without prior treatment (treatment naïve) and Cohort B2 comprising 157 women or men with prior treatment (pretreated).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ribociclib + letrozole cohort A
    Arm description
    postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.
    Arm type
    Experimental

    Investigational medicinal product name
    ribociclib and letrozole
    Investigational medicinal product code
    ribociclib (LEE011)
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib - 600 mg (3 x 200mg) - Once daily - Days 1-21 of each 28-day cycle; Letrozole - 2.5 mg - Once daily

    Arm title
    ribociclib + letrozole cohort B1
    Arm description
    premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly
    Arm type
    Experimental

    Investigational medicinal product name
    Ribociclib and Letrozole and Goserelin (for premenopausal patients)
    Investigational medicinal product code
    ribociclib (LEE011)
    Other name
    Pharmaceutical forms
    Tablet, Implant
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    Ribociclib - 600 mg (3 x 200mg) - Once daily - Days 1-21 of each 28-day cycle; Letrozole - 2.5 mg - Once daily; Goserelin (for premenopausal patients) - 3.6 mg - Day 1 of each cycle

    Arm title
    ribociclib + letrozole cohort B2
    Arm description
    premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly
    Arm type
    Experimental

    Investigational medicinal product name
    Ribociclib and Letrozole and Goserelin (for premenopausal patients)
    Investigational medicinal product code
    ribociclib (LEE011)
    Other name
    Pharmaceutical forms
    Tablet, Implant
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    Ribociclib - 600 mg (3 x 200mg) - Once daily - Days 1-21 of each 28-day cycle; Letrozole - 2.5 mg - Once daily; Goserelin (for premenopausal patients) - 3.6 mg - Day 1 of each cycle

    Number of subjects in period 1
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Started
    319
    26
    157
    Completed
    100
    6
    19
    Not completed
    219
    20
    138
         Progressive disease
    97
    10
    78
         Protocol deviation
    3
    -
    6
         Physician decision
    12
    2
    8
         New therapy for study indication
    1
    -
    1
         Non-compliance with study medication
    1
    -
    -
         Adverse event, serious fatal
    6
    -
    2
         Adverse event, non-fatal
    72
    6
    28
         not specified
    2
    1
    2
         Consent withdrawn by subject
    24
    1
    12
         Lost to follow-up
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ribociclib + letrozole cohort A
    Reporting group description
    postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

    Reporting group title
    ribociclib + letrozole cohort B1
    Reporting group description
    premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Reporting group title
    ribociclib + letrozole cohort B2
    Reporting group description
    premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Reporting group values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2 Total
    Number of subjects
    319 26 157 502
    Age Categorical
    Units: Participants
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    143 26 87 256
        >=65 years
    176 0 70 246
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    65.7 ± 10.1 46.5 ± 4.9 62.8 ± 12.8 -
    Sex: Female, Male
    Units: Participants
        Female
    315 26 156 497
        Male
    4 0 1 5
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 1 1 2
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 1 0 1
        White
    312 24 151 487
        More than one race
    1 0 3 4
        Unknown or Not Reported
    6 0 2 8

    End points

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    End points reporting groups
    Reporting group title
    ribociclib + letrozole cohort A
    Reporting group description
    postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

    Reporting group title
    ribociclib + letrozole cohort B1
    Reporting group description
    premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Reporting group title
    ribociclib + letrozole cohort B2
    Reporting group description
    premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Subject analysis set title
    ribociclib + letrozole cohort A
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

    Subject analysis set title
    ribociclib + letrozole cohort B
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    premenopausal women or perimenopausal women or postmenopausal women, or men; naïve + pre-treated All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o.daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Subject analysis set title
    ribociclib + letrozole cohort B1
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Subject analysis set title
    ribociclib + letrozole cohort B2
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Subject analysis set title
    Total
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Total

    Primary: Clinical Benefit Rate (CBR) in women and men with hormone receptor positiv, HER-2 negative breast cancer treated with ribocilib and letrozole

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    End point title
    Clinical Benefit Rate (CBR) in women and men with hormone receptor positiv, HER-2 negative breast cancer treated with ribocilib and letrozole [1]
    End point description
    Clinical Benefit Rate (CBR) after 24 weeks of treatment as defined by RECIST 1.1 as percentage of patients with Complete Response (CR), Partial response (PR) or Stable disease (SD) lasting 24 weeks or longer as well as patients with NCRNPD >24 for patients with non-measurable disease
    End point type
    Primary
    End point timeframe
    At 24 weeks after last patient enrolled in trial
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Summary statistics is available although statistical analysis is not.
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B Total
    Number of subjects analysed
    307
    180
    487
    Units: Percentage of Participants
    number (confidence interval 95%)
        CBR by week 24)(Confirmed BOR)
    63.2 (57.5 to 68.6)
    56.7 (49.1 to 64.0)
    60.8 (56.3 to 65.1)
        CBR by week 24(non-confirmed BOR)
    71.7 (66.3 to 76.6)
    65.0 (57.6 to 71.9)
    69.2 (64.9 to 73.3)
    No statistical analyses for this end point

    Secondary: CBR

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    End point title
    CBR
    End point description
    To assess the CBR after 24 weeks among pre- and perimenopausal women without prior therapy for advanced disease (Cohort B1); To assess the CBR after 24 weeks for ribociclib among pre-, peri- and postmenopausal women and men who were pretreated for advanced disease (Cohort B2)
    End point type
    Secondary
    End point timeframe
    At 24 weeks
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    0 [2]
    26
    154
    Units: Percentage of Participants
    number (confidence interval 95%)
        CBR by week 24 – confirmed assessment
    ( to )
    57.7 (36.9 to 76.6)
    56.5 (48.3 to 64.5)
        CBR by week 24 – unconfirmed assessment
    ( to )
    69.2 (48.2 to 85.7)
    64.3 (56.2 to 71.8)
    Notes
    [2] - measure not applicable for this arm.
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) for different populations - Kaplan-Meier estimates (%, 95% CI)

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    End point title
    Progression free survival (PFS) for different populations - Kaplan-Meier estimates (%, 95% CI)
    End point description
    PFS based on radiologic assessment by investigator using RECIST 1.1 criteria
    End point type
    Secondary
    End point timeframe
    At week 24 , week 48 and week 72
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    307
    26
    154
    Units: Percentage of Participants
    number (confidence interval 95%)
        Kaplan-Meier estimates (%, 95% CI) - Week 24
    73.1 (67.3 to 77.9)
    67.0 (44.7 to 82.0)
    63.8 (55.2 to 71.3)
        Kaplan-Meier estimates (%, 95% CI) - Week 48
    61.9 (55.7 to 67.5)
    58.7 (36.8 to 75.2)
    47.5 (38.7 to 55.7)
        Kaplan-Meier estimates (%, 95% CI) - week 72
    54.5 (48.1 to 60.5)
    49.6 (28.6 to 67.6)
    39.3 (30.8 to 47.6)
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) for different populations - Median time to progression or death with 95% CI [months]

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    End point title
    Progression free survival (PFS) for different populations - Median time to progression or death with 95% CI [months]
    End point description
    PFS based on radiologic assessment by investigator using RECIST 1.1 criteria
    End point type
    Secondary
    End point timeframe
    Up to approximately month 25
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    307
    26
    154
    Units: Months
        median (confidence interval 95%)
    21.8 (13.9 to 25.3)
    16.5 (3.2 to 999)
    8.8 (8.1 to 16.3)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - Kaplan-Meier estimates (%, 95% CI)

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    End point title
    Overall Survival (OS) - Kaplan-Meier estimates (%, 95% CI)
    End point description
    Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    At Week 24, Week 48 and Week 72
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    307
    26
    154
    Units: Percentage of Participants
    number (confidence interval 95%)
        Kaplan-Meier estimates (%, 95% CI) - Week 24
    98.6 (96.4 to 99.5)
    100.0 (100.0 to 100.0)
    93.9 (88.5 to 96.8)
        Kaplan-Meier estimates (%, 95% CI) - Week 48
    93.3 (89.7 to 95.7)
    87.5 (66.1 to 95.8)
    86.1 (79.2 to 90.8)
        Kaplan-Meier estimates (%, 95% CI) - Week 72
    89.7 (85.5 to 92.7)
    87.5 (66.1 to 95.8)
    81.0 (73.5 to 86.6)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - Median time to progression or death with 95% CI [months]

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    End point title
    Overall Survival (OS) - Median time to progression or death with 95% CI [months]
    End point description
    Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Up to approximatley 38 months
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    307
    26
    154
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (30.9 to 999)
    999 (31.0 to 999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - number of deaths

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    End point title
    Overall Survival (OS) - number of deaths
    End point description
    Overall survival (OS) defined as the time from date of start of treatment to date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Up to approximatley 38 months
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    307
    26
    154
    Units: Participants
        No. of censored (no death), n
    240
    17
    94
        No. of events (deaths due to any cause), n
    67
    9
    60
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) - Kaplan-Meier estimates (%, 95% CI)

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    End point title
    Overall response rate (ORR) - Kaplan-Meier estimates (%, 95% CI)
    End point description
    Overall response rate (ORR) defined as complete response or partial response as defined by RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At week 24
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    307
    26
    154
    Units: Percentage of Participants
    number (confidence interval 95%)
        ORR by week 24 - (BOR of CR or PR) (confirmed)
    22.8 (18.2 to 27.9)
    23.1 (9.0 to 43.6)
    11.7 (7.1 to 17.8)
        ORR by week 24 - (BOR of CR or PR) (unconfirmed)
    24.8 (20.0 to 30.0)
    30.8 (14.3 to 51.8)
    16.2 (10.8 to 23.0)
    No statistical analyses for this end point

    Secondary: Patient reported Quality of Life (QoL) via EORTC QLQ-C30

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    End point title
    Patient reported Quality of Life (QoL) via EORTC QLQ-C30
    End point description
    The QLQ-C30 is the core questionnaire of the EORTC QLQ, which has been developed for the assessment of the health-related QOL of cancer patients participating in international clinical trials (Aaronson et al. 1993). Using a linear transformation to standardize the raw scores, all scores finally range from 0 to 100, where a higher score represents a higher response level, e.g., a higher ("better") level of functioning, but a higher ("worse") level of symptoms (Fayers et al. 2001). There is no aggregated total score, i.e., all scale scores were analyzed separately.
    End point type
    Secondary
    End point timeframe
    Change from Baseline to Week 24
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B
    Number of subjects analysed
    307
    154
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Global health status-Change from b/l to Wk 24
    8.8 ± 23.7
    5.0 ± 26.2
        Physical Functioning-Change from b/l to Wk 24
    -3.1 ± 19.9
    -2.2 ± 17.7
        Role Functioning-Change from b/l to Wk 24
    -6.6 ± 31.9
    -1.3 ± 34.7
        Emotional Functioning-Change from b/l to Wk 24
    -9.6 ± 24.2
    -3.6 ± 21.8
        Cognitive Functioning-Change from b/l to Wk 24
    2.7 ± 23.7
    1.1 ± 21.6
        Social Functioning-Change from b/l to Wk 24
    -6.9 ± 27.9
    -5.3 ± 31.3
        Fatigue - Change from baseline to Wk 24
    6.3 ± 25.9
    3.9 ± 27.1
        Nausea / Vomiting-Change from b/l to Wk 24
    0.1 ± 16.7
    -4.9 ± 19.1
        Pain-Change from baseline to Wk 24
    13.2 ± 31.9
    9.0 ± 27.6
        Dyspnoea-Change from baseline to Wk 24
    3.8 ± 32.4
    -5.3 ± 30.5
        Insomnia-Change from baseline to Wk 24
    4.2 ± 33.2
    4.9 ± 32.7
        Appetite loss-Change from baseline to Wk 24
    11.2 ± 33.7
    1.4 ± 30.9
        Constipation-Change from baseline to Wk 24
    -2.7 ± 26.6
    -3.6 ± 27.9
        Diarrhea-Change from baseline to Wk 24
    2.6 ± 24.6
    2.3 ± 27.2
        Financial Problems-Change from b/l to Wk 24
    0.2 ± 27.7
    -1.4 ± 25.1
    No statistical analyses for this end point

    Secondary: Patient reported Quality of Life (QoL) via EORTC BR-23 - change from baseline at Week 24 (Cycle 7)

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    End point title
    Patient reported Quality of Life (QoL) via EORTC BR-23 - change from baseline at Week 24 (Cycle 7)
    End point description
    To evaluate health related quality of life (QoL) via EORTC BR-23. The scoring approach for the QLQ-BR23 is identical in principle to that for the function and symptom scales / single items of the QLQ-C30, i.e., all scores finally range from 0 to 100, where a higher score represents a higher response level, e.g., a higher ("better") level of functioning, but a higher ("worse") level of symptoms (Fayers et al. 2001).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (Cycle 7)
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B
    Number of subjects analysed
    307
    154
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        BODY IMAGE - change from b/l at cycle 7
    -1.5 ± 18.2
    0.4 ± 22.7
        SEXUAL FUNCTIONING - change from b/l at cycle 7
    -1.1 ± 17.7
    0.8 ± 18.0
        SEXUAL ENJOYMENT - change from b/l at cycle 7
    -1.9 ± 31.3
    7.4 ± 26.9
        FUTURE PERSPECTIVE - change from b/l at cycle 7
    -20 ± 33.4
    -12 ± 26.2
        SYSTEMATIC THERAPY - change from b/l at cycle 7
    -9.4 ± 16.6
    -6.0 ± 14.9
        BREAST SYMPTOMS - change from b/l at cycle 7
    3.3 ± 15.7
    0.9 ± 17.5
        ARM SYMPTOMS - change from b/l at cycle 7
    4.1 ± 21.1
    -2.1 ± 18.1
        HAIR LOSS - change from baseline at cycle 7
    -22 ± 43.4
    -14 ± 33.9
    No statistical analyses for this end point

    Secondary: To evaluate the safety and tolerability of ribociclib in combination with letrozole (and goserelin in premenopausal patients) - via collection of Treatment Emergent Adverse Events (TEAE)

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    End point title
    To evaluate the safety and tolerability of ribociclib in combination with letrozole (and goserelin in premenopausal patients) - via collection of Treatment Emergent Adverse Events (TEAE)
    End point description
    AEs were separated into TEAEs (defined as AEs occurring/worsening from first study drug treatment until 30 days after the last study drug treatment) and AEs in the pre-/post-treatment period.
    End point type
    Secondary
    End point timeframe
    Up to Week 72
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2
    Number of subjects analysed
    319
    26
    157
    Units: Number of Participants
        Total AEs
    318
    25
    157
        Serious AE
    97
    5
    45
        Non-serious AE
    317
    25
    157
        AE with suspected relationship to ribociclib
    302
    25
    144
        AE leading to discontinuation of ribociclib
    76
    7
    38
        AE with fatal outcome
    6
    0
    6
    No statistical analyses for this end point

    Secondary: Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status

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    End point title
    Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status
    End point description
    Time to 10% deterioration in the European Organisation for Research and Treatment of Cancer (EORTC) global health status
    End point type
    Secondary
    End point timeframe
    up to approximately 10 months
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2 Total
    Number of subjects analysed
    307
    26
    154
    487
    Units: months
        median (confidence interval 95%)
    3.3 (2.8 to 4.6)
    3.7 (1.8 to 10.1)
    2.8 (1.8 to 4.6)
    3.0 (2.8 to 4.6)
    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
    On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 1150 days (approx 3.15 years). (Treatment duration ranged from 2 days to 1120 days). Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 3.15 years. Patients who didn’t die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
    End point type
    Post-hoc
    End point timeframe
    on-treatment deaths: up to approx 3.15 years; all deaths: approx 3.15 years
    End point values
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B Total
    Number of subjects analysed
    319 [3]
    183 [4]
    502 [5]
    Units: Participants
        on-treatment deaths
    6
    6
    12
        Total deaths
    67
    69
    136
    Notes
    [3] - n = 319 for on-treatment deaths; n = 307 for total deaths
    [4] - n = 183 for on-treatment deaths; n = 180 for total deaths
    [5] - n = 502 for on-treatment deaths; n = 487 for total deaths
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days, up to a maximum duration of 1150 days (approx. 3.15 years).(Treatment duration ranged from 2 days to 1120 days.)
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    ribociclib + letrozole cohort A
    Reporting group description
    postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

    Reporting group title
    ribociclib + letrozole cohort B
    Reporting group description
    premenopausal women or perimenopausal women or postmenopausal women, or men; naïve + pre-treated All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o.daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Reporting group title
    ribociclib + letrozole cohort B1
    Reporting group description
    premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Reporting group title
    ribociclib + letrozole cohort B2
    Reporting group description
    premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

    Reporting group title
    Total
    Reporting group description
    Total

    Serious adverse events
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2 Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    97 / 319 (30.41%)
    50 / 183 (27.32%)
    5 / 26 (19.23%)
    45 / 157 (28.66%)
    147 / 502 (29.28%)
         number of deaths (all causes)
    6
    6
    0
    6
    12
         number of deaths resulting from adverse events
    1
    1
    0
    1
    2
    Vascular disorders
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BRONCHIAL CARCINOMA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CANCER PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLON CANCER
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT PLEURAL EFFUSION
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO BONE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO SPINE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL CELL CARCINOMA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF THE TONGUE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    1 / 26 (3.85%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMPLICATION OF DEVICE INSERTION
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    FATIGUE
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 319 (0.63%)
    5 / 183 (2.73%)
    0 / 26 (0.00%)
    5 / 157 (3.18%)
    7 / 502 (1.39%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 5
    0 / 0
    2 / 5
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IMPAIRED HEALING
         subjects affected / exposed
    1 / 319 (0.31%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    6 / 319 (1.88%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    7 / 502 (1.39%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 1
    0 / 0
    0 / 1
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANIC ATTACK
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SOMATIC SYMPTOM DISORDER
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    PELVIC PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ACCIDENT
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    1 / 26 (3.85%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CERVICAL VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INCISIONAL HERNIA
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JAW FRACTURE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    1 / 26 (3.85%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST-TRAUMATIC PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE ADHESION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROCEDURAL COMPLICATION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TIBIA FRACTURE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 319 (1.57%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    6 / 502 (1.20%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
    0 / 0
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 319 (0.94%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    4 / 502 (0.80%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    1 / 26 (3.85%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    1 / 26 (3.85%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 319 (0.63%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    4 / 502 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRADYARRHYTHMIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    9 / 319 (2.82%)
    3 / 183 (1.64%)
    0 / 26 (0.00%)
    3 / 157 (1.91%)
    12 / 502 (2.39%)
         occurrences causally related to treatment / all
    3 / 10
    0 / 3
    0 / 0
    0 / 3
    3 / 13
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    1 / 2
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERVENTILATION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    3 / 319 (0.94%)
    3 / 183 (1.64%)
    0 / 26 (0.00%)
    3 / 157 (1.91%)
    6 / 502 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    PNEUMONITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    7 / 319 (2.19%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    8 / 502 (1.59%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
    0 / 0
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    PULMONARY FIBROSIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 319 (1.25%)
    4 / 183 (2.19%)
    0 / 26 (0.00%)
    4 / 157 (2.55%)
    8 / 502 (1.59%)
         occurrences causally related to treatment / all
    10 / 11
    10 / 12
    0 / 0
    10 / 12
    20 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DISSEMINATED INTRAVASCULAR COAGULATION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 319 (0.00%)
    3 / 183 (1.64%)
    1 / 26 (3.85%)
    2 / 157 (1.27%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    HYPERFIBRINOLYSIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    2 / 319 (0.63%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    4 / 502 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MONOPLEGIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL NERVE LESION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    0 / 0
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL HAEMORRHAGE
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 319 (0.94%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    4 / 502 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    INTESTINAL STRANGULATION
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    7 / 319 (2.19%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    9 / 502 (1.79%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 3
    0 / 0
    0 / 3
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    VOMITING
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    5 / 319 (1.57%)
    1 / 183 (0.55%)
    1 / 26 (3.85%)
    0 / 157 (0.00%)
    6 / 502 (1.20%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 1
    1 / 1
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    HAEMATURIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    KIDNEY CONGESTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL DISORDER
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETERIC STENOSIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY INCONTINENCE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT OBSTRUCTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STENOSIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BILIARY COLIC
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    5 / 319 (1.57%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    6 / 502 (1.20%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 1
    0 / 0
    1 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATOTOXICITY
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JAUNDICE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    DEVICE LOOSENING
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BONE LESION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    2 / 319 (0.63%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    4 / 502 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FLANK PAIN
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MOBILITY DECREASED
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEITIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEONECROSIS OF JAW
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL PAIN
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOPHAGIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUMOUR LYSIS SYNDROME
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL ABSCESS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABSCESS JAW
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS INFECTIVE
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS ESCHERICHIA
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    DIVERTICULITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EMPHYSEMATOUS CHOLECYSTITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA INFECTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEBRILE INFECTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HELICOBACTER GASTRITIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    8 / 319 (2.51%)
    2 / 183 (1.09%)
    0 / 26 (0.00%)
    2 / 157 (1.27%)
    10 / 502 (1.99%)
         occurrences causally related to treatment / all
    2 / 8
    1 / 2
    0 / 0
    1 / 2
    3 / 10
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    1 / 1
    1 / 3
    PROTEUS INFECTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY SYNCYTIAL VIRUS INFECTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 319 (0.31%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    1 / 502 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    3 / 502 (0.60%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 183 (0.00%)
    0 / 26 (0.00%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ribociclib + letrozole cohort A ribociclib + letrozole cohort B ribociclib + letrozole cohort B1 ribociclib + letrozole cohort B2 Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    315 / 319 (98.75%)
    181 / 183 (98.91%)
    25 / 26 (96.15%)
    156 / 157 (99.36%)
    496 / 502 (98.80%)
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    44 / 319 (13.79%)
    30 / 183 (16.39%)
    11 / 26 (42.31%)
    19 / 157 (12.10%)
    74 / 502 (14.74%)
         occurrences all number
    49
    35
    13
    22
    84
    HYPERTENSION
         subjects affected / exposed
    36 / 319 (11.29%)
    11 / 183 (6.01%)
    4 / 26 (15.38%)
    7 / 157 (4.46%)
    47 / 502 (9.36%)
         occurrences all number
    38
    13
    4
    9
    51
    Immune system disorders
    SEASONAL ALLERGY
         subjects affected / exposed
    4 / 319 (1.25%)
    6 / 183 (3.28%)
    3 / 26 (11.54%)
    3 / 157 (1.91%)
    10 / 502 (1.99%)
         occurrences all number
    4
    6
    3
    3
    10
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    123 / 319 (38.56%)
    74 / 183 (40.44%)
    15 / 26 (57.69%)
    59 / 157 (37.58%)
    197 / 502 (39.24%)
         occurrences all number
    151
    86
    16
    70
    237
    OEDEMA PERIPHERAL
         subjects affected / exposed
    35 / 319 (10.97%)
    22 / 183 (12.02%)
    5 / 26 (19.23%)
    17 / 157 (10.83%)
    57 / 502 (11.35%)
         occurrences all number
    37
    31
    7
    24
    68
    PYREXIA
         subjects affected / exposed
    23 / 319 (7.21%)
    14 / 183 (7.65%)
    4 / 26 (15.38%)
    10 / 157 (6.37%)
    37 / 502 (7.37%)
         occurrences all number
    31
    19
    7
    12
    50
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    7 / 319 (2.19%)
    8 / 183 (4.37%)
    2 / 26 (7.69%)
    6 / 157 (3.82%)
    15 / 502 (2.99%)
         occurrences all number
    9
    8
    2
    6
    17
    INSOMNIA
         subjects affected / exposed
    31 / 319 (9.72%)
    26 / 183 (14.21%)
    4 / 26 (15.38%)
    22 / 157 (14.01%)
    57 / 502 (11.35%)
         occurrences all number
    34
    28
    5
    23
    62
    SLEEP DISORDER
         subjects affected / exposed
    13 / 319 (4.08%)
    10 / 183 (5.46%)
    4 / 26 (15.38%)
    6 / 157 (3.82%)
    23 / 502 (4.58%)
         occurrences all number
    15
    10
    4
    6
    25
    Reproductive system and breast disorders
    VULVOVAGINAL DRYNESS
         subjects affected / exposed
    4 / 319 (1.25%)
    3 / 183 (1.64%)
    3 / 26 (11.54%)
    0 / 157 (0.00%)
    7 / 502 (1.39%)
         occurrences all number
    5
    3
    3
    0
    8
    Injury, poisoning and procedural complications
    ARTHROPOD BITE
         subjects affected / exposed
    3 / 319 (0.94%)
    3 / 183 (1.64%)
    2 / 26 (7.69%)
    1 / 157 (0.64%)
    6 / 502 (1.20%)
         occurrences all number
    3
    3
    2
    1
    6
    ARTHROPOD STING
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 183 (1.09%)
    2 / 26 (7.69%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences all number
    0
    2
    2
    0
    2
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    75 / 319 (23.51%)
    36 / 183 (19.67%)
    6 / 26 (23.08%)
    30 / 157 (19.11%)
    111 / 502 (22.11%)
         occurrences all number
    93
    43
    10
    33
    136
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    66 / 319 (20.69%)
    36 / 183 (19.67%)
    5 / 26 (19.23%)
    31 / 157 (19.75%)
    102 / 502 (20.32%)
         occurrences all number
    82
    44
    8
    36
    126
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    16 / 319 (5.02%)
    1 / 183 (0.55%)
    0 / 26 (0.00%)
    1 / 157 (0.64%)
    17 / 502 (3.39%)
         occurrences all number
    17
    1
    0
    1
    18
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    27 / 319 (8.46%)
    12 / 183 (6.56%)
    2 / 26 (7.69%)
    10 / 157 (6.37%)
    39 / 502 (7.77%)
         occurrences all number
    38
    13
    2
    11
    51
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    17 / 319 (5.33%)
    3 / 183 (1.64%)
    1 / 26 (3.85%)
    2 / 157 (1.27%)
    20 / 502 (3.98%)
         occurrences all number
    22
    4
    1
    3
    26
    BLOOD THYROID STIMULATING HORMONE INCREASED
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 183 (1.09%)
    2 / 26 (7.69%)
    0 / 157 (0.00%)
    2 / 502 (0.40%)
         occurrences all number
    0
    2
    2
    0
    2
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    23 / 319 (7.21%)
    14 / 183 (7.65%)
    1 / 26 (3.85%)
    13 / 157 (8.28%)
    37 / 502 (7.37%)
         occurrences all number
    29
    19
    1
    18
    48
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    33 / 319 (10.34%)
    18 / 183 (9.84%)
    5 / 26 (19.23%)
    13 / 157 (8.28%)
    51 / 502 (10.16%)
         occurrences all number
    38
    20
    5
    15
    58
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    40 / 319 (12.54%)
    25 / 183 (13.66%)
    2 / 26 (7.69%)
    23 / 157 (14.65%)
    65 / 502 (12.95%)
         occurrences all number
    164
    75
    2
    73
    239
    WEIGHT DECREASED
         subjects affected / exposed
    16 / 319 (5.02%)
    9 / 183 (4.92%)
    0 / 26 (0.00%)
    9 / 157 (5.73%)
    25 / 502 (4.98%)
         occurrences all number
    17
    12
    0
    12
    29
    WEIGHT INCREASED
         subjects affected / exposed
    7 / 319 (2.19%)
    4 / 183 (2.19%)
    2 / 26 (7.69%)
    2 / 157 (1.27%)
    11 / 502 (2.19%)
         occurrences all number
    7
    5
    3
    2
    12
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    27 / 319 (8.46%)
    18 / 183 (9.84%)
    2 / 26 (7.69%)
    16 / 157 (10.19%)
    45 / 502 (8.96%)
         occurrences all number
    56
    21
    2
    19
    77
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    53 / 319 (16.61%)
    22 / 183 (12.02%)
    6 / 26 (23.08%)
    16 / 157 (10.19%)
    75 / 502 (14.94%)
         occurrences all number
    66
    26
    7
    19
    92
    DYSPNOEA
         subjects affected / exposed
    49 / 319 (15.36%)
    25 / 183 (13.66%)
    4 / 26 (15.38%)
    21 / 157 (13.38%)
    74 / 502 (14.74%)
         occurrences all number
    58
    26
    4
    22
    84
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    11 / 319 (3.45%)
    7 / 183 (3.83%)
    5 / 26 (19.23%)
    2 / 157 (1.27%)
    18 / 502 (3.59%)
         occurrences all number
    12
    9
    7
    2
    21
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    46 / 319 (14.42%)
    36 / 183 (19.67%)
    7 / 26 (26.92%)
    29 / 157 (18.47%)
    82 / 502 (16.33%)
         occurrences all number
    60
    60
    19
    41
    120
    LEUKOPENIA
         subjects affected / exposed
    76 / 319 (23.82%)
    39 / 183 (21.31%)
    8 / 26 (30.77%)
    31 / 157 (19.75%)
    115 / 502 (22.91%)
         occurrences all number
    183
    108
    45
    63
    291
    LYMPHOPENIA
         subjects affected / exposed
    7 / 319 (2.19%)
    2 / 183 (1.09%)
    2 / 26 (7.69%)
    0 / 157 (0.00%)
    9 / 502 (1.79%)
         occurrences all number
    14
    13
    13
    0
    27
    NEUTROPENIA
         subjects affected / exposed
    162 / 319 (50.78%)
    88 / 183 (48.09%)
    15 / 26 (57.69%)
    73 / 157 (46.50%)
    250 / 502 (49.80%)
         occurrences all number
    558
    326
    95
    231
    884
    THROMBOCYTOPENIA
         subjects affected / exposed
    26 / 319 (8.15%)
    18 / 183 (9.84%)
    1 / 26 (3.85%)
    17 / 157 (10.83%)
    44 / 502 (8.76%)
         occurrences all number
    46
    23
    2
    21
    69
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    26 / 319 (8.15%)
    12 / 183 (6.56%)
    4 / 26 (15.38%)
    8 / 157 (5.10%)
    38 / 502 (7.57%)
         occurrences all number
    30
    17
    8
    9
    47
    DYSGEUSIA
         subjects affected / exposed
    20 / 319 (6.27%)
    11 / 183 (6.01%)
    4 / 26 (15.38%)
    7 / 157 (4.46%)
    31 / 502 (6.18%)
         occurrences all number
    21
    12
    4
    8
    33
    HEADACHE
         subjects affected / exposed
    56 / 319 (17.55%)
    36 / 183 (19.67%)
    10 / 26 (38.46%)
    26 / 157 (16.56%)
    92 / 502 (18.33%)
         occurrences all number
    90
    55
    20
    35
    145
    HYPOAESTHESIA
         subjects affected / exposed
    3 / 319 (0.94%)
    5 / 183 (2.73%)
    3 / 26 (11.54%)
    2 / 157 (1.27%)
    8 / 502 (1.59%)
         occurrences all number
    3
    5
    3
    2
    8
    POLYNEUROPATHY
         subjects affected / exposed
    16 / 319 (5.02%)
    5 / 183 (2.73%)
    1 / 26 (3.85%)
    4 / 157 (2.55%)
    21 / 502 (4.18%)
         occurrences all number
    17
    5
    1
    4
    22
    Eye disorders
    DRY EYE
         subjects affected / exposed
    23 / 319 (7.21%)
    10 / 183 (5.46%)
    2 / 26 (7.69%)
    8 / 157 (5.10%)
    33 / 502 (6.57%)
         occurrences all number
    24
    11
    2
    9
    35
    LACRIMATION INCREASED
         subjects affected / exposed
    34 / 319 (10.66%)
    11 / 183 (6.01%)
    2 / 26 (7.69%)
    9 / 157 (5.73%)
    45 / 502 (8.96%)
         occurrences all number
    38
    11
    2
    9
    49
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    33 / 319 (10.34%)
    17 / 183 (9.29%)
    4 / 26 (15.38%)
    13 / 157 (8.28%)
    50 / 502 (9.96%)
         occurrences all number
    41
    17
    4
    13
    58
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    15 / 319 (4.70%)
    14 / 183 (7.65%)
    5 / 26 (19.23%)
    9 / 157 (5.73%)
    29 / 502 (5.78%)
         occurrences all number
    21
    17
    7
    10
    38
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    33 / 319 (10.34%)
    13 / 183 (7.10%)
    3 / 26 (11.54%)
    10 / 157 (6.37%)
    46 / 502 (9.16%)
         occurrences all number
    42
    20
    7
    13
    62
    CONSTIPATION
         subjects affected / exposed
    62 / 319 (19.44%)
    32 / 183 (17.49%)
    4 / 26 (15.38%)
    28 / 157 (17.83%)
    94 / 502 (18.73%)
         occurrences all number
    71
    43
    4
    39
    114
    DIARRHOEA
         subjects affected / exposed
    85 / 319 (26.65%)
    40 / 183 (21.86%)
    8 / 26 (30.77%)
    32 / 157 (20.38%)
    125 / 502 (24.90%)
         occurrences all number
    133
    57
    16
    41
    190
    DRY MOUTH
         subjects affected / exposed
    28 / 319 (8.78%)
    10 / 183 (5.46%)
    1 / 26 (3.85%)
    9 / 157 (5.73%)
    38 / 502 (7.57%)
         occurrences all number
    30
    10
    1
    9
    40
    DYSPEPSIA
         subjects affected / exposed
    25 / 319 (7.84%)
    14 / 183 (7.65%)
    2 / 26 (7.69%)
    12 / 157 (7.64%)
    39 / 502 (7.77%)
         occurrences all number
    28
    14
    2
    12
    42
    NAUSEA
         subjects affected / exposed
    130 / 319 (40.75%)
    77 / 183 (42.08%)
    9 / 26 (34.62%)
    68 / 157 (43.31%)
    207 / 502 (41.24%)
         occurrences all number
    202
    108
    11
    97
    310
    STOMATITIS
         subjects affected / exposed
    33 / 319 (10.34%)
    27 / 183 (14.75%)
    4 / 26 (15.38%)
    23 / 157 (14.65%)
    60 / 502 (11.95%)
         occurrences all number
    40
    30
    4
    26
    70
    TOOTHACHE
         subjects affected / exposed
    9 / 319 (2.82%)
    4 / 183 (2.19%)
    2 / 26 (7.69%)
    2 / 157 (1.27%)
    13 / 502 (2.59%)
         occurrences all number
    10
    4
    2
    2
    14
    VOMITING
         subjects affected / exposed
    66 / 319 (20.69%)
    31 / 183 (16.94%)
    5 / 26 (19.23%)
    26 / 157 (16.56%)
    97 / 502 (19.32%)
         occurrences all number
    93
    63
    10
    53
    156
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    119 / 319 (37.30%)
    57 / 183 (31.15%)
    5 / 26 (19.23%)
    52 / 157 (33.12%)
    176 / 502 (35.06%)
         occurrences all number
    127
    63
    7
    56
    190
    DRY SKIN
         subjects affected / exposed
    24 / 319 (7.52%)
    15 / 183 (8.20%)
    3 / 26 (11.54%)
    12 / 157 (7.64%)
    39 / 502 (7.77%)
         occurrences all number
    27
    16
    3
    13
    43
    ERYTHEMA
         subjects affected / exposed
    9 / 319 (2.82%)
    10 / 183 (5.46%)
    1 / 26 (3.85%)
    9 / 157 (5.73%)
    19 / 502 (3.78%)
         occurrences all number
    9
    10
    1
    9
    19
    PRURITUS
         subjects affected / exposed
    45 / 319 (14.11%)
    18 / 183 (9.84%)
    3 / 26 (11.54%)
    15 / 157 (9.55%)
    63 / 502 (12.55%)
         occurrences all number
    53
    19
    4
    15
    72
    RASH
         subjects affected / exposed
    47 / 319 (14.73%)
    19 / 183 (10.38%)
    2 / 26 (7.69%)
    17 / 157 (10.83%)
    66 / 502 (13.15%)
         occurrences all number
    60
    25
    3
    22
    85
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    57 / 319 (17.87%)
    39 / 183 (21.31%)
    9 / 26 (34.62%)
    30 / 157 (19.11%)
    96 / 502 (19.12%)
         occurrences all number
    76
    47
    12
    35
    123
    BACK PAIN
         subjects affected / exposed
    37 / 319 (11.60%)
    24 / 183 (13.11%)
    4 / 26 (15.38%)
    20 / 157 (12.74%)
    61 / 502 (12.15%)
         occurrences all number
    42
    29
    6
    23
    71
    BONE PAIN
         subjects affected / exposed
    35 / 319 (10.97%)
    15 / 183 (8.20%)
    6 / 26 (23.08%)
    9 / 157 (5.73%)
    50 / 502 (9.96%)
         occurrences all number
    42
    18
    9
    9
    60
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    12 / 319 (3.76%)
    6 / 183 (3.28%)
    2 / 26 (7.69%)
    4 / 157 (2.55%)
    18 / 502 (3.59%)
         occurrences all number
    13
    7
    2
    5
    20
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    21 / 319 (6.58%)
    14 / 183 (7.65%)
    2 / 26 (7.69%)
    12 / 157 (7.64%)
    35 / 502 (6.97%)
         occurrences all number
    27
    15
    3
    12
    42
    MYALGIA
         subjects affected / exposed
    18 / 319 (5.64%)
    6 / 183 (3.28%)
    0 / 26 (0.00%)
    6 / 157 (3.82%)
    24 / 502 (4.78%)
         occurrences all number
    18
    7
    0
    7
    25
    PAIN IN EXTREMITY
         subjects affected / exposed
    52 / 319 (16.30%)
    23 / 183 (12.57%)
    3 / 26 (11.54%)
    20 / 157 (12.74%)
    75 / 502 (14.94%)
         occurrences all number
    68
    35
    5
    30
    103
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    44 / 319 (13.79%)
    19 / 183 (10.38%)
    1 / 26 (3.85%)
    18 / 157 (11.46%)
    63 / 502 (12.55%)
         occurrences all number
    45
    20
    1
    19
    65
    HYPERKALAEMIA
         subjects affected / exposed
    6 / 319 (1.88%)
    4 / 183 (2.19%)
    2 / 26 (7.69%)
    2 / 157 (1.27%)
    10 / 502 (1.99%)
         occurrences all number
    18
    6
    4
    2
    24
    HYPOCALCAEMIA
         subjects affected / exposed
    8 / 319 (2.51%)
    5 / 183 (2.73%)
    2 / 26 (7.69%)
    3 / 157 (1.91%)
    13 / 502 (2.59%)
         occurrences all number
    10
    5
    2
    3
    15
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    19 / 319 (5.96%)
    5 / 183 (2.73%)
    1 / 26 (3.85%)
    4 / 157 (2.55%)
    24 / 502 (4.78%)
         occurrences all number
    25
    6
    1
    5
    31
    CYSTITIS
         subjects affected / exposed
    21 / 319 (6.58%)
    9 / 183 (4.92%)
    3 / 26 (11.54%)
    6 / 157 (3.82%)
    30 / 502 (5.98%)
         occurrences all number
    25
    10
    3
    7
    35
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    2 / 319 (0.63%)
    3 / 183 (1.64%)
    2 / 26 (7.69%)
    1 / 157 (0.64%)
    5 / 502 (1.00%)
         occurrences all number
    2
    3
    2
    1
    5
    NASOPHARYNGITIS
         subjects affected / exposed
    94 / 319 (29.47%)
    49 / 183 (26.78%)
    10 / 26 (38.46%)
    39 / 157 (24.84%)
    143 / 502 (28.49%)
         occurrences all number
    131
    74
    18
    56
    205
    URINARY TRACT INFECTION
         subjects affected / exposed
    31 / 319 (9.72%)
    17 / 183 (9.29%)
    1 / 26 (3.85%)
    16 / 157 (10.19%)
    48 / 502 (9.56%)
         occurrences all number
    45
    23
    2
    21
    68

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2016
    The purpose of this amendment was to include feedback received from BfArM and ECs during the assessment of the initial application.
    03 May 2017
    This amendment was intended to update the existing information about ribociclib, to clarify specific aspects of the original protocol and to introduce the option for treatment beyond radiologic progression at the investigators discretion.
    14 Aug 2017
    This amendment was intended to correct mistakes in the protocol
    05 May 2019
    This amendment was intended to update the existing information about ribociclib, to clarify specific aspects of the original protocol and to introduce the option for treatment beyond radiologic progression at the investigators discretion.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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