Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   43935   clinical trials with a EudraCT protocol, of which   7309   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    COMPLEEMENT-1: An open-label, multicenter, Phase IIIb study to assess the safety and efficacy of ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (aBC) with no prior hormonal therapy for advanced disease

    Summary
    EudraCT number
    2016-003467-19
    Trial protocol
    BE   GB   NL   HU   BG   PT   GR   SK   IT   CZ   AT   ES   DK   NO   PL   FI   SI   RO   LU  
    Global end of trial date
    09 Nov 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Oct 2023
    First version publication date
    12 Oct 2023
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CLEE011A2404
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02941926
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus,, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the safety and tolerability of ribociclib + letrozole in men and pre/postmenopausal women with HR+, HER2- aBC who received no prior hormonal therapy for advanced disease.
    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
    30 Nov 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
    Argentina: 25
    Country: Number of subjects enrolled
    Austria: 30
    Country: Number of subjects enrolled
    Belgium: 228
    Country: Number of subjects enrolled
    Bulgaria: 52
    Country: Number of subjects enrolled
    Canada: 251
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Czechia: 65
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Finland: 22
    Country: Number of subjects enrolled
    France: 306
    Country: Number of subjects enrolled
    Greece: 29
    Country: Number of subjects enrolled
    Hong Kong: 14
    Country: Number of subjects enrolled
    Hungary: 40
    Country: Number of subjects enrolled
    India: 103
    Country: Number of subjects enrolled
    Israel: 42
    Country: Number of subjects enrolled
    Italy: 554
    Country: Number of subjects enrolled
    Jordan: 20
    Country: Number of subjects enrolled
    Lebanon: 17
    Country: Number of subjects enrolled
    Malaysia: 28
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Netherlands: 130
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Oman: 2
    Country: Number of subjects enrolled
    Panama: 4
    Country: Number of subjects enrolled
    Philippines: 14
    Country: Number of subjects enrolled
    Poland: 64
    Country: Number of subjects enrolled
    Portugal: 53
    Country: Number of subjects enrolled
    Russian Federation: 129
    Country: Number of subjects enrolled
    Saudi Arabia: 10
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Slovakia: 14
    Country: Number of subjects enrolled
    Slovenia: 33
    Country: Number of subjects enrolled
    Spain: 526
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Thailand: 17
    Country: Number of subjects enrolled
    United Kingdom: 139
    Country: Number of subjects enrolled
    United States: 208
    Worldwide total number of subjects
    3246
    EEA total number of subjects
    2178
    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)
    2173
    From 65 to 84 years
    1049
    85 years and over
    24

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Core Phase was conducted across 514 centers in 38 countries. Extension Phase was conducted across 189 centers in 25 countries.

    Pre-assignment
    Screening details
    A total of 3694 participants were screened in this study of which 3246 participants were enrolled in the study.

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Ribociclib + letrozole + goserelin/leuprolide
    Arm description
    Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
    Arm type
    Experimental

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    LEE011
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib 200 mg tablets were centrally supplied to the investigators and administered orally once a day on days 1-21 of each 28-day cycle at a starting dose of 600 mg daily.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was procured locally and administered orally once a day on a continuous daily schedule at a dose of 2.5 mg.

    Investigational medicinal product name
    Goserelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Goserelin was procured locally and administered in men and premenopausal women as an injectable subcutaneous implant administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 3.6 mg.

    Investigational medicinal product name
    Leuprolide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Leuprolide was procured locally and administered in men and premenopausal women as an injectable intramuscular depot administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 7.5 mg.

    Number of subjects in period 1
    Ribociclib + letrozole + goserelin/leuprolide
    Started
    3246
    Completed
    1301
    Not completed
    1945
         Adverse event, serious fatal
    46
         Physician decision
    112
         Adverse event, non-fatal
    504
         Technical problems
    5
         Protocol deviation
    34
         Progressive disease
    1109
         Lost to follow-up
    8
         Subject/guardian decision
    127
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Ribociclib + letrozole + goserelin/leuprolide
    Arm description
    Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
    Arm type
    Experimental

    Investigational medicinal product name
    Ribociclib
    Investigational medicinal product code
    LEE011
    Other name
    Pharmaceutical forms
    Tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribociclib 200 mg tablets were centrally supplied to the investigators and administered orally once a day on days 1-21 of each 28-day cycle at a starting dose of 600 mg daily.

    Investigational medicinal product name
    Leuprolide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Leuprolide was procured locally and administered in men and premenopausal women as an injectable intramuscular depot administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 7.5 mg

    Investigational medicinal product name
    Goserelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Goserelin was procured locally and administered in men and premenopausal women as an injectable subcutaneous implant administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 3.6 mg.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was procured locally and administered orally once a day on a continuous daily schedule at a dose of 2.5 mg.

    Number of subjects in period 2 [1]
    Ribociclib + letrozole + goserelin/leuprolide
    Started
    413
    Completed
    112
    Not completed
    301
         Adverse event, serious fatal
    6
         Physician decision
    155
         Adverse event, non-fatal
    13
         Progressive disease
    115
         Subject/guardian decision
    12
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only patients who were deriving benefit at the end of the Core phase and ribociclib was not approved or available and reimbursed, were transitioned to the Extension Phase

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Ribociclib + letrozole + goserelin/leuprolide
    Reporting group description
    Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.

    Reporting group values
    Ribociclib + letrozole + goserelin/leuprolide Total
    Number of subjects
    3246 3246
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    2173 2173
        From 65-84 years
    1049 1049
        85 years and over
    24 24
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    58.1 ± 12.22 -
    Sex: Female, Male
    Units: Participants
        Female
    3207 3207
        Male
    39 39
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    2553 2553
        Unknown
    284 284
        Asian
    227 227
        Other
    134 134
        Black
    29 29
        Native American
    18 18
        Pacific Islander
    1 1

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Ribociclib + letrozole + goserelin/leuprolide
    Reporting group description
    Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.
    Reporting group title
    Ribociclib + letrozole + goserelin/leuprolide
    Reporting group description
    Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection.

    Primary: Number of participants with adverse events (AEs) and Serious AEs (SAEs) during treatment with ribociclib + letrozole in the Core phase

    Close Top of page
    End point title
    Number of participants with adverse events (AEs) and Serious AEs (SAEs) during treatment with ribociclib + letrozole in the Core phase [1]
    End point description
    AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. A SAE which caused death of the participant was considered as fatal SAE. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.
    End point type
    Primary
    End point timeframe
    From start of treatment up to 30 days after last treatment (for participants who did not enter to the Extension phase) or up to last treatment in the Core phase (for participants who entered the Extension phase), assessed up to approximately 33 months.
    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: No statistical analyses were planned for the primary endpoint
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    3246
    Units: Participants
        AEs- All grades
    3203
        AEs- Grade ≥ 3
    2461
        Treatment-related AEs (TRAEs)- All grades
    3091
        TRAEs- Grade ≥ 3
    2192
        SAEs- All grades
    702
        SAEs- Grade ≥ 3
    590
        Treatment-related SAEs (TRSAEs)- All grades
    203
        TRSAEs- Grade ≥ 3
    178
        Fatal SAEs- All grades
    62
        Treatment-related Fatal SAEs- All grades
    14
        AEs leading to discontinuation- All grades
    528
        AEs leading to discontinuation- Grade ≥ 3
    310
        TRAEs leading to discontinuation- All grades
    418
        TRAEs leading to discontinuation-Grade ≥ 3
    237
        AEs leading to dose modifications- All grades
    2434
        AEs leading to dose modifications- Grade ≥ 3
    2095
        TRAEs leading to dose modifications- All grades
    2235
        TRAEs leading to dose modifications- Grade ≥ 3
    1964
        AEs requiring additional therapy- All grades
    2624
        AEs requiring additional therapy- Grade ≥ 3
    844
        TRAEs requiring additional therapy- All grades
    1613
        TRAEs requiring additional therapy- Grade ≥ 3
    392
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) based on investigator's assessment (Core phase)

    Close Top of page
    End point title
    Overall response rate (ORR) based on investigator's assessment (Core phase)
    End point description
    Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. 95% CI was calculated using the exact binomial method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 33 months
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    3246
    Units: Percentage of participants
        number (confidence interval 95%)
    29.3 (27.7 to 30.9)
    No statistical analyses for this end point

    Secondary: Time-to-Progression (TTP) based on investigator's assessment (Core phase)

    Close Top of page
    End point title
    Time-to-Progression (TTP) based on investigator's assessment (Core phase)
    End point description
    Time to progression (TTP) is defined as time from date of start of treatment to the date of first documented progression or death due to underlying cancer. Participants with symptoms of rapidly progressing disease without radiologic evidence were classified as progression only when clear evidence of clinical deterioration was documented and/or patient discontinued due to ‘Disease progression’ or death due to study indication. When there was no documentation of radiologic evidence of progression, and the patient discontinued for ‘Disease progression’ due to documented clinical deterioration of disease, the date of discontinuation was used as date of progression. TTP was estimated using the Kaplan-Meier method. 95% CI of median was calculated according to Brookmeyer and Crowley method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 33 months
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    3246
    Units: Months
        median (confidence interval 95%)
    27.1 (25.7 to 9999)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) based on investigator's assessment (Core phase)

    Close Top of page
    End point title
    Clinical Benefit Rate (CBR) based on investigator's assessment (Core phase)
    End point description
    Clinical benefit rate (CBR) is defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. CR, PR and SD are defined according to RECIST 1.1 based on investigator's assessment. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease. 95% CI was calculated using the exact binomial method.
    End point type
    Secondary
    End point timeframe
    Up to approximately 33 months
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    3246
    Units: Percentage of participants
        number (confidence interval 95%)
    70.7 (69.1 to 72.2)
    No statistical analyses for this end point

    Secondary: Change from baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) score (Core phase)

    Close Top of page
    End point title
    Change from baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) score (Core phase)
    End point description
    Change from baseline in FACT-B scores was assessed. FACT-B is a self-report instrument that measures multidimensional quality of life (QOL) in patients with breast cancer. The FACT-B consists of 37 questions that address physical, social, emotional, and functional well-being, with specific questions relevant to women with breast cancer. Each item has a score range of 0 (Not at all) to 4 (Very much), with a total score ranging from 0-148. The higher the score, the better the QOL reported by the participant. A positive change from baseline indicates improvement in QoL. Due to the nature of the questionnaire, only females were asked to complete this questionnaire.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycle 1, 2, 3, 4 ,5, 6, 8, 10, 12 and after that every 3 cycles, and End of treatment, assessed up to 33 months. Cycle=28 days
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    1230
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1
    0.2 ± 13.29
        Cycle 3 Day 1
    0.1 ± 13.72
        Cycle 4 Day 1
    -0.3 ± 14.90
        Cycle 5 Day 1
    0.0 ± 15.02
        Cycle 6 Day 1
    -0.8 ± 14.91
        Cycle 8 Day 1
    -0.9 ± 16.32
        Cycle 10 Day 1
    -1.2 ± 15.83
        Cycle 12 Day 1
    -1.6 ± 16.13
        Cycle 15 Day 1
    -2.0 ± 16.58
        Cycle 18 Day 1
    -2.0 ± 16.09
        Cycle 21 Day 1
    -2.0 ± 17.82
        Cycle 24 Day 1
    -3.0 ± 17.89
        Cycle 27 Day 1
    -2.7 ± 13.84
        Cycle 30 Day 1
    -2.0 ± 14.14
        Cycle 33 Day 1
    12.1 ± 21.10
        End of Treatment
    -4.1 ± 16.98
    No statistical analyses for this end point

    Secondary: Number of participants with AEs and SAEs in the Extension phase

    Close Top of page
    End point title
    Number of participants with AEs and SAEs in the Extension phase
    End point description
    AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.
    End point type
    Secondary
    End point timeframe
    From first dose of treatment in the Extension phase up to 30 days after last dose of treatment, assessed up approximately 37.6 months
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    413
    Units: Participants
        AEs- All grades
    297
        AEs- Grade ≥ 3
    159
        Treatment-related AEs (TRAEs)- All grades
    221
        TRAEs- Grade ≥ 3
    123
        SAEs- All grades
    54
        SAEs- Grade ≥ 3
    45
        Treatment-related SAEs (TRSAEs)- All grades
    7
        TRSAEs- Grade ≥ 3
    6
        Fatal SAEs- All grades
    5
        Treatment-related Fatal SAEs- All grades
    0
        AEs leading to discontinuation- All grades
    17
        AEs leading to discontinuation- Grade ≥ 3
    9
        TRAEs leading to discontinuation- All grades
    7
        TRAEs leading to discontinuation-Grade ≥ 3
    4
        AEs leading to dose modifications- All grades
    185
        AEs leading to dose modifications- Grade ≥ 3
    132
        TRAEs leading to dose modifications- All grades
    134
        TRAEs leading to dose modifications- Grade ≥ 3
    113
        AEs requiring additional therapy- All grades
    186
        AEs requiring additional therapy- Grade ≥ 3
    56
        TRAEs requiring additional therapy- All grades
    47
        TRAEs requiring additional therapy- Grade ≥ 3
    12
    No statistical analyses for this end point

    Secondary: Number of participants with clinical benefit (Extension phase)

    Close Top of page
    End point title
    Number of participants with clinical benefit (Extension phase)
    End point description
    Clinical benefit as assessed by the Investigator during Extension phase
    End point type
    Secondary
    End point timeframe
    On Day 1 of every 3 cycles, starting from Cycle 1 of the Extension phase until end of treatment, assessed up to 37.4 months. Cycle= 28 days
    End point values
    Ribociclib + letrozole + goserelin/leuprolide
    Number of subjects analysed
    413
    Units: Participants
        Cycle 1 Day 1
    413
        Cycle 4 Day 1
    386
        Cycle 7 Day 1
    353
        Cycle 10 Day 1
    323
        Cycle 13 Day 1
    245
        Cycle 16 Day 1
    200
        Cycle 19 Day 1
    183
        Cycle 22 Day 1
    118
        Cycle 25 Day 1
    55
        Cycle 28 Day 1
    51
        Cycle 31 Day 1
    44
        Cycle 34 Day 1
    32
        Cycle 37 Day 1
    24
        Cycle 40 Day 1
    5
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Core: First dose to 30 days after last treatment (non-Extension participants) or last treatment in the Core (Extension participants), assessed up to 33 months. Extension: First dose to 30 days after last treatment, assessed up to approx. 37.6 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    All patients- Extension phase
    Reporting group description
    AEs collected during the Extension phase (from first dose of treatment in the Extension phase up to 30 days after last dose of treatment)

    Reporting group title
    All patients- Core phase
    Reporting group description
    AEs collected in the core phase of the study (up to 30 days after last treatment for participants who did not enter the Extension phase or up to last treatment in the Core phase for participants who entered the Extension phase)

    Serious adverse events
    All patients- Extension phase All patients- Core phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 413 (13.08%)
    702 / 3246 (21.63%)
         number of deaths (all causes)
    5
    74
         number of deaths resulting from adverse events
    0
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Adenocarcinoma of the cervix
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 413 (0.24%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast cancer recurrent
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic cancer
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leiomyoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ependymoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of pleura
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Malignant pleural effusion
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cancer
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein embolism
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 413 (0.00%)
    13 / 3246 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 14
         deaths causally related to treatment / all
    0 / 0
    1 / 4
    Gait disturbance
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza like illness
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 413 (0.24%)
    9 / 3246 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Malaise
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organ failure
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pre-existing condition improved
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 413 (0.24%)
    25 / 3246 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    7 / 25
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sudden death
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Strangulated hernia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Menopause
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopause
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Colpocele
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 413 (0.48%)
    45 / 3246 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    9 / 47
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 413 (0.24%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 413 (0.00%)
    19 / 3246 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 413 (0.00%)
    8 / 3246 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumomediastinum
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 413 (0.00%)
    34 / 3246 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory gas exchange disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 413 (0.24%)
    8 / 3246 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Respiratory distress
         subjects affected / exposed
    1 / 413 (0.24%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery stenosis
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apathy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervousness
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device extrusion
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 413 (0.00%)
    15 / 3246 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    12 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 413 (0.00%)
    23 / 3246 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    19 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 413 (0.00%)
    10 / 3246 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Waist circumference increased
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycoplasma test positive
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Electrocardiogram change
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biopsy liver abnormal
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 413 (0.24%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 413 (0.48%)
    8 / 3246 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation of wound
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    10 / 3246 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation skin injury
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Tibia fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning deliberate
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic valve incompetence
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Atrioventricular block complete
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 413 (0.00%)
    7 / 3246 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 413 (0.24%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cor pulmonale
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Coronary artery stenosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 413 (0.24%)
    9 / 3246 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Coma
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 413 (0.00%)
    7 / 3246 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paralysis recurrent laryngeal nerve
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    24 / 3246 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    17 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 413 (0.00%)
    21 / 3246 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    16 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 413 (0.00%)
    9 / 3246 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 413 (0.24%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 413 (0.00%)
    8 / 3246 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eyelid ptosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amaurosis fugax
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 413 (0.24%)
    16 / 3246 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain upper
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 413 (0.00%)
    14 / 3246 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal obstruction
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 413 (0.00%)
    12 / 3246 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic artery aneurysm
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal stenosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stomatitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 413 (0.48%)
    31 / 3246 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    17 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Drug-induced liver injury
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatitis toxic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 413 (0.00%)
    12 / 3246 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder necrosis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 413 (0.24%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal impairment
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 413 (0.00%)
    8 / 3246 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 413 (0.73%)
    21 / 3246 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 413 (0.00%)
    7 / 3246 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rigidity
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 413 (0.00%)
    6 / 3246 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 413 (0.00%)
    9 / 3246 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 413 (0.24%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholinitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 413 (0.24%)
    10 / 3246 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 413 (0.00%)
    9 / 3246 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gallbladder empyema
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal fungal infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 413 (0.48%)
    12 / 3246 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia influenzal
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 413 (1.21%)
    35 / 3246 (1.08%)
         occurrences causally related to treatment / all
    1 / 7
    8 / 37
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Post procedural infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 413 (0.00%)
    3 / 3246 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Sepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    12 / 3246 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Spinal cord infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 413 (0.24%)
    17 / 3246 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 413 (0.73%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    5 / 413 (1.21%)
    0 / 3246 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 413 (0.00%)
    5 / 3246 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 3246 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    8 / 3246 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    4 / 3246 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 413 (0.00%)
    9 / 3246 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypophosphataemia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mineral metabolism disorder
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 3246 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All patients- Extension phase All patients- Core phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    247 / 413 (59.81%)
    3150 / 3246 (97.04%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 413 (2.42%)
    523 / 3246 (16.11%)
         occurrences all number
    10
    657
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 413 (2.91%)
    456 / 3246 (14.05%)
         occurrences all number
    13
    566
    White blood cell count decreased
         subjects affected / exposed
    21 / 413 (5.08%)
    336 / 3246 (10.35%)
         occurrences all number
    35
    665
    Neutrophil count decreased
         subjects affected / exposed
    29 / 413 (7.02%)
    623 / 3246 (19.19%)
         occurrences all number
    70
    1670
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 413 (0.73%)
    217 / 3246 (6.69%)
         occurrences all number
    3
    263
    Blood creatinine increased
         subjects affected / exposed
    6 / 413 (1.45%)
    199 / 3246 (6.13%)
         occurrences all number
    7
    271
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 413 (1.94%)
    490 / 3246 (15.10%)
         occurrences all number
    9
    519
    Hypertension
         subjects affected / exposed
    11 / 413 (2.66%)
    227 / 3246 (6.99%)
         occurrences all number
    13
    272
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 413 (4.84%)
    458 / 3246 (14.11%)
         occurrences all number
    26
    635
    Dizziness
         subjects affected / exposed
    13 / 413 (3.15%)
    235 / 3246 (7.24%)
         occurrences all number
    14
    277
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    13 / 413 (3.15%)
    254 / 3246 (7.83%)
         occurrences all number
    19
    455
    Neutropenia
         subjects affected / exposed
    116 / 413 (28.09%)
    1981 / 3246 (61.03%)
         occurrences all number
    294
    5908
    Lymphopenia
         subjects affected / exposed
    4 / 413 (0.97%)
    165 / 3246 (5.08%)
         occurrences all number
    6
    239
    Leukopenia
         subjects affected / exposed
    23 / 413 (5.57%)
    596 / 3246 (18.36%)
         occurrences all number
    38
    1259
    Anaemia
         subjects affected / exposed
    22 / 413 (5.33%)
    597 / 3246 (18.39%)
         occurrences all number
    25
    843
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 413 (2.91%)
    627 / 3246 (19.32%)
         occurrences all number
    12
    789
    Fatigue
         subjects affected / exposed
    14 / 413 (3.39%)
    756 / 3246 (23.29%)
         occurrences all number
    15
    885
    Oedema peripheral
         subjects affected / exposed
    2 / 413 (0.48%)
    279 / 3246 (8.60%)
         occurrences all number
    2
    320
    Pyrexia
         subjects affected / exposed
    25 / 413 (6.05%)
    393 / 3246 (12.11%)
         occurrences all number
    26
    497
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    5 / 413 (1.21%)
    237 / 3246 (7.30%)
         occurrences all number
    5
    265
    Diarrhoea
         subjects affected / exposed
    18 / 413 (4.36%)
    684 / 3246 (21.07%)
         occurrences all number
    20
    1019
    Constipation
         subjects affected / exposed
    11 / 413 (2.66%)
    553 / 3246 (17.04%)
         occurrences all number
    12
    663
    Abdominal pain upper
         subjects affected / exposed
    1 / 413 (0.24%)
    216 / 3246 (6.65%)
         occurrences all number
    1
    251
    Abdominal pain
         subjects affected / exposed
    7 / 413 (1.69%)
    213 / 3246 (6.56%)
         occurrences all number
    7
    259
    Nausea
         subjects affected / exposed
    21 / 413 (5.08%)
    1160 / 3246 (35.74%)
         occurrences all number
    27
    1628
    Vomiting
         subjects affected / exposed
    18 / 413 (4.36%)
    633 / 3246 (19.50%)
         occurrences all number
    19
    1045
    Stomatitis
         subjects affected / exposed
    4 / 413 (0.97%)
    291 / 3246 (8.96%)
         occurrences all number
    4
    364
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    10 / 413 (2.42%)
    275 / 3246 (8.47%)
         occurrences all number
    10
    303
    Cough
         subjects affected / exposed
    10 / 413 (2.42%)
    492 / 3246 (15.16%)
         occurrences all number
    11
    585
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 413 (1.45%)
    374 / 3246 (11.52%)
         occurrences all number
    7
    472
    Pruritus
         subjects affected / exposed
    2 / 413 (0.48%)
    431 / 3246 (13.28%)
         occurrences all number
    2
    543
    Dry skin
         subjects affected / exposed
    5 / 413 (1.21%)
    228 / 3246 (7.02%)
         occurrences all number
    5
    246
    Alopecia
         subjects affected / exposed
    4 / 413 (0.97%)
    638 / 3246 (19.65%)
         occurrences all number
    4
    663
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 413 (0.48%)
    274 / 3246 (8.44%)
         occurrences all number
    2
    291
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    5 / 413 (1.21%)
    192 / 3246 (5.91%)
         occurrences all number
    5
    212
    Musculoskeletal pain
         subjects affected / exposed
    1 / 413 (0.24%)
    205 / 3246 (6.32%)
         occurrences all number
    1
    231
    Bone pain
         subjects affected / exposed
    9 / 413 (2.18%)
    225 / 3246 (6.93%)
         occurrences all number
    10
    256
    Back pain
         subjects affected / exposed
    22 / 413 (5.33%)
    426 / 3246 (13.12%)
         occurrences all number
    24
    514
    Arthralgia
         subjects affected / exposed
    38 / 413 (9.20%)
    674 / 3246 (20.76%)
         occurrences all number
    43
    893
    Pain in extremity
         subjects affected / exposed
    14 / 413 (3.39%)
    263 / 3246 (8.10%)
         occurrences all number
    16
    320
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 413 (1.69%)
    194 / 3246 (5.98%)
         occurrences all number
    10
    237
    Urinary tract infection
         subjects affected / exposed
    16 / 413 (3.87%)
    195 / 3246 (6.01%)
         occurrences all number
    26
    279
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 413 (2.91%)
    191 / 3246 (5.88%)
         occurrences all number
    17
    235
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 413 (1.69%)
    401 / 3246 (12.35%)
         occurrences all number
    7
    442

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2016
    Premenopausal patients (receiving concomitant ovarian suppression with goserelin) were allowed to be included in the study, based on current treatment guidelines. Male patients entering the study were also required to use goserelin concurrently with ribociclib + letrozole based on the current standard of care in this patient population. The end of the Core Phase was defined as 18 months after LPFV. Secondary objectives and the associated end points for Extension Phase were stated. Dose modification guidelines were updated
    16 Aug 2017
    Expansion of another monthly-based dosing LHRH agonist (leuprolide) in addition to goserelin, based on NCCN Breast Cancer Guidelines 2017. Removal of requirement for prior anti-cancer therapy, 5 half-lives, washout period. Clarification of the sample size calculation: 3000 patients were planned to be enrolled in this study to detect rare AEs (frequency ~0.1%) with high probability.
    24 Sep 2018
    Updated the language regarding early study termination by the sponsor. Updated withdrawal of consent language with the new Global Data Protection Requirements. Updated the dose adjustment and management recommendations for QTcF prolongation, as analyses of preclinical and clinical data with ribociclib have demonstrated that ribociclib prolongs the QT interval in a concentration-dependent manner. Updated the list of prohibited medications during study treatment, and co-medication considerations. Updated the list of medications to be used with caution during study drug treatment period
    23 Jan 2020
    Updated safety information on ribociclib in alignment with LEE011 (Ribociclib) Investigator’s Brochure (IB), Edition 14 (release date: 28-Nov-2019) and definition of the duration of the Extension Phase and transition plan for patients during and at the end of the study. Significant changes included: Addition of ribociclib dose adjustment and management recommendation for interstitial lung disease/pneumonitis, which was observed with CDK4/6 inhibitor treatment as a class effect; Addition of guidance to discontinue ribociclib if toxic epidermal necrolysis is diagnosed; Updated tables relating to hepatic and cardiac QTc monitoring; Updated the lists of prohibited medications and medications to be used with caution during study treatment; Updated the language regarding Extension Phase duration (defined as 18 months after LPLV of the Core Phase) and transition plan

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/ for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA