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    Clinical Trial Results:
    monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib plus Trastuzumab with or without Fulvestrant to Standard-of-Care Chemotherapy of Physician?s Choice plus Trastuzumab in Women with HR+, HER2+ Locally Advanced or Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2015-003400-24
    Trial protocol
    		 ES   GR   BE   GB   DE   IT  
    Global end of trial date
    09 Nov 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Nov 2024
    First version publication date
    24 Apr 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    New Data added to full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    I3Y-MC-JPBZ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02675231
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 15804
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    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 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the effectiveness of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus physicians choice standard of care chemotherapy in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) locally advanced or metastatic breast cancer after prior exposure to at least two HER2-directed therapies for advanced disease.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 May 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: 19
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 30
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 7
    Worldwide total number of subjects
    237
    EEA total number of subjects
    111
    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)
    185
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In the Subject disposition, completers included participants who either died due to any cause or were alive and on the study at the conclusion but off treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Arm description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    LY2835219
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Arm title
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Arm description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    LY2835219
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg abemaciclib given orally Q12H of a 21-day cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Arm title
    		 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Arm description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Investigational medicinal product name
    Standard of Care Single Agent Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard-of-care single-agent chemotherapy of physician’s choice administered according to product label

    Number of subjects in period 1
    		150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Started
    79
    79
    79
    Received at Least One Dose of Drug
    78
    77
    72 [1]
    Completed
    74
    71
    74
    Not completed
    5
    8
    5
         Consent withdrawn by subject
    2
    4
    2
         Lost to follow-up
    3
    4
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone is added to represent the treated participants.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Reporting group description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Reporting group description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Reporting group title
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Reporting group description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.

    Reporting group values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy Total
    Number of subjects
    		 79 79 79 237
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.34 ( 10.25 ) 54.99 ( 11.08 ) 56.77 ( 12.37 ) -
    Gender categorical
    Units: Subjects
        Female
    		 79 79 79 237
        Male
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 11 12 37
        Not Hispanic or Latino
    		 58 52 56 166
        Unknown or Not Reported
    		 7 16 11 34
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1 2
        Asian
    		 15 10 10 35
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 3 2 4 9
        White
    		 55 53 55 163
        More than one race
    		 0 0 1 1
        Unknown or Not Reported
    		 6 13 8 27
    Region of Enrollment
    Units: Subjects
        Argentina
    		 9 7 3 19
        United States
    		 20 8 17 45
        United Kingdom
    		 9 9 10 28
        Spain
    		 6 8 3 17
        Greece
    		 1 1 2 4
        Canada
    		 2 4 4 10
        South Korea
    		 11 9 10 30
        Belgium
    		 5 7 7 19
        Brazil
    		 3 1 4 8
        Italy
    		 2 5 2 9
        Mexico
    		 2 1 3 6
        Australia
    		 2 4 2 8
        France
    		 6 13 8 27
        Germany
    		 1 2 4 7

    End points

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    End points reporting groups
    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Reporting group description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Reporting group description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Reporting group title
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Reporting group description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS time was measured from the date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. Analysis Population Description (APD) included all enrolled participants.
    End point type
    Primary
    End point timeframe
    Baseline to Progressive Disease or Death from Any Cause (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79 [1]
    79 [2]
    79 [3]
    Units: Months
        median (confidence interval 95%)
    8.3 (5.9 to 12.6)
    5.7 (4.2 to 7.2)
    5.7 (5.4 to 6.9)
    Notes
    [1] - Censored participants: =23
    [2] - Censored participants: =18
    [3] - Censored participants: =27
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.
    Comparison groups
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy v 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0506 [5]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.
    [5] - This is statistically significant at the pre-specified 2-sided alpha of 0·2
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.7695
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.

    Secondary: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)

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    End point title
    		 Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
    End point description
    ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Objective Disease Progression (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    32.9 (22.5 to 43.3)
    13.9 (6.3 to 21.6)
    13.9 (6.3 to 21.6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    DoR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. APD included all enrolled participants who received at least one dose of study drug and achieved CR or PR. 99999=NA because for 8 mg/kg Trastuzumab + Standard of Care Chemotherapy, the median and upper limit of the 95% CI was not calculated due to the high censoring rate.
    End point type
    Secondary
    End point timeframe
    Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    26 [7]
    11 [8]
    11 [9]
    Units: Months
        median (confidence interval 95%)
    12.5 (6.5 to 23.5)
    9.5 (2.8 to 22.7)
    99999 (4.1 to 99999)
    Notes
    [7] - Censored participants: =12
    [8] - Censored participants: =3
    [9] - Censored participants: =11 99999 = NA.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)

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    End point title
    		 Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)
    End point description
    Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Objective Disease Progression (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    78.5 (69.4 to 87.5)
    74.7 (65.1 to 84.3)
    67.1 (56.7 to 77.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Best Overall Response of CR, PR, or SD with Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR)

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    End point title
    		 Percentage of Participants with Best Overall Response of CR, PR, or SD with Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR)
    End point description
    Clinical benefit rate defined as percentage of participants with best overall response of CR, PR, or SD with a duration of at least 6 months. CR, PR, or SD were defined using RECIST, v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Percentage of participants = (participants with CR+PR+SD with a duration of at least 6 months /number of participants enrolled) *100. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Date of CR, PR or SD to 6 Months Post CR, PR or SD (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    58.2 (47.4 to 69.1)
    45.6 (34.6 to 56.6)
    38.0 (27.3 to 48.7)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf)

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    End point title
    		 Change from Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf)
    End point description
    The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity. In addition to pain intensity (4 items), the mBPI-sf is designed for participants to record the presence of pain in general, pain relief, and pain interference with function (general activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, enjoyment of life). Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales anchored at 0 (no pain or does not interfere) and 10 (pain as bad as you can imagine or completely interferes). The mBPI-sf recall period is 24 hours and typical completion time for this instrument is less than 5 minutes. Mean Interference Score data is reported here. Least square (LS) Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: units on a scale
        least squares mean (standard error)
    0 ( 0.18 )
    0.20 ( 0.18 )
    0.31 ( 0.19 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.232 [10]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [10] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.

    Secondary: Change from Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)

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    End point title
    		 Change from Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30 v3.0 was a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all randomized participants who received at least one dose of study drug with baseline and post-baseline EORTC QLQ-C30 data for each EORTC QLQ-C30 items.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    72
    72
    69
    Units: units on a scale
    least squares mean (standard error)
        Global health status
    -2.9 ( 1.6 )
    -5.9 ( 1.7 )
    -1.9 ( 1.8 )
        Functional scale: Physical functioning
    -1.0 ( 1.6 )
    -4.4 ( 1.6 )
    -4.5 ( 1.7 )
        Functional scale: Role functioning
    -2.7 ( 2.2 )
    -5.0 ( 2.3 )
    -8.2 ( 2.4 )
        Functional scale: Emotional functioning
    2.4 ( 1.7 )
    -0.4 ( 1.8 )
    1.1 ( 1.8 )
        Functional scale: Cognitive functioning
    -1.8 ( 1.4 )
    -1.1 ( 1.5 )
    -1.6 ( 1.6 )
        Functional scale: Social functioning
    -0.9 ( 1.9 )
    -0.9 ( 1.9 )
    -2.4 ( 2.0 )
        Symptom scale: Fatigue
    1.8 ( 1.9 )
    7.0 ( 2.0 )
    4.7 ( 2.1 )
        Symptom scale: Nausea and vomiting
    6.3 ( 1.4 )
    5.6 ( 1.4 )
    2.2 ( 1.5 )
        Symptom scale: Pain
    -2.5 ( 2.1 )
    3.1 ( 2.1 )
    4.3 ( 2.2 )
        Symptom scale: Dyspnoea
    0.7 ( 1.9 )
    2.9 ( 2.0 )
    3.7 ( 2.1 )
        Symptom scale: Insomnia
    -4.4 ( 2.1 )
    -1.6 ( 2.2 )
    2.0 ( 2.3 )
        Symptom scale: Appetite loss
    6.3 ( 2.3 )
    5.5 ( 2.4 )
    2.4 ( 2.5 )
        Symptom scale: Constipation
    -6.3 ( 1.9 )
    -10.5 ( 1.9 )
    -3.4 ( 2.0 )
        Symptom scale: Diarrhoea
    21.5 ( 2.2 )
    25.3 ( 2.3 )
    2.2 ( 2.4 )
        Symptom scale: Financial difficulties
    0.8 ( 2.0 )
    -1.9 ( 2.1 )
    -3.2 ( 2.2 )
    Statistical analysis title
    		 Statistical Analysis 1: Global health status
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.689 [11]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [11] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 2: Functional scale: Physical
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.141 [12]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [12] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 3: Functional scale: Role
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.095 [13]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [13] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical analysis 4:Functional scale: Emotional
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.591 [14]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [14] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 5: Functional scale:Cognitive
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.935 [15]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [15] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical analysis 6: Functional scale: Social
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.578 [16]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [16] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 7: Symptom scale: Fatigue
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.308 [17]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [17] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 8 : Symptom: Nausea, vomiting
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043 [18]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [18] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 9: Symptom scale: Pain
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026 [19]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [19] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 10: Symptom scale: Dyspnoea
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276 [20]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [20] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 11: Symptom scale: Insomnia
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041 [21]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [21] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 12: Symptom: Appetite loss
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.262 [22]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [22] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 13:Symptom scale:Constipation
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.285
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [23] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 14: Symptom scale: Diarrhoea
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [24]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [24] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 15: Symptom scale: Financial
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18 [25]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [25] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.

    Secondary: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

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    End point title
    		 Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
    End point description
    The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. Five dimensions of health status are each assessed with 5 response options and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status.LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all enrolled participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    72
    72
    68
    Units: units on a scale
        least squares mean (standard error)
    0.01 ( 0.02 )
    -0.01 ( 0.02 )
    -0.04 ( 0.02 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033 [26]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [26] - p-values are from Type 3 sums of squares mixed models repeated measures model: Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.275 [27]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [27] - p-values are from Type 3 sums of squares mixed models repeated measures model: Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.

    Secondary: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS)

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    End point title
    		 Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS)
    End point description
    European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. The EQ-5D-5L is assessed using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. A higher score indicates better health state. LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all enrolled participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L VAS data.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    72
    71
    70
    Units: millimeter (mm)
        least squares mean (standard error)
    0.61 ( 1.4 )
    -1.64 ( 1.4 )
    -0.61 ( 1.5 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.546
    Method
    		 MMRM Model
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy v 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.62
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [28] - EQ 5D-5L Visual Analog Scale Score

    Secondary: Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and its Metabolites (M2 and M20)

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    End point title
    		 Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and its Metabolites (M2 and M20) [29]
    End point description
    Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) was evaluated. M2 and M20 are 2 major active metabolites of abemaciclib.
    End point type
    Secondary
    End point timeframe
    Cycle(C)1 Day(D)1,C1D15, C2D1, C2D8, C3D1,C3D15, C4D1, C5D1:pre-dose; C1D1, C2D1, C3D1, C4D1, C5D1:post-dose
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The outcome is specific to Abemaciclib and its Metabolites
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Number of subjects analysed
    77
    71
    Units: nanogram/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Abemaciclib
    134 ( 77 )
    155 ( 53 )
        M2
    72.0 ( 120 )
    96.5 ( 120 )
        M20
    136 ( 120 )
    181 ( 130 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With 1 Year Overall Survival (OS)

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    End point title
    		 Percentage of Participants With 1 Year Overall Survival (OS)
    End point description
    OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 1 year from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method. APD included all randomized participants (including the censored participants).
    End point type
    Secondary
    End point timeframe
    Randomization to date of death from any cause assessed at 1 year
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79 [30]
    79 [31]
    79 [32]
    Units: percentage of participants
        number (confidence interval 95%)
    77.2 (65.9 to 85.2)
    77.4 (66.1 to 85.3)
    69.8 (57.5 to 79.1)
    Notes
    [30] - Censored participants: = 62
    [31] - Censored participants: = 62
    [32] - Censored participants: = 58
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified by the number of previous regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of disease (measurable vs. non-measurable).
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.241
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.3
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified by the number of previous regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of disease (measurable vs. non-measurable).
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.313
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.36

    Secondary: Percentage of Participants With 2 Year OS

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    End point title
    		 Percentage of Participants With 2 Year OS
    End point description
    OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 2 years from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method. APD included all randomized participants (including the censored participants).
    End point type
    Secondary
    End point timeframe
    Randomization to date of death from any cause assessed at 2 years
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79 [33]
    79 [34]
    79 [35]
    Units: percentage of participants
        number (confidence interval 95%)
    55.8 (43.5 to 66.4)
    55.7 (43.4 to 66.3)
    43.0 (30.9 to 54.5)
    Notes
    [33] - Censored participants: = 47
    [34] - Censored participants: = 47
    [35] - Censored participants: = 41
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified by the number of previous regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of disease (measurable vs. non-measurable).
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.104
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.08
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified by the number of previous regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of disease (measurable vs. non-measurable).
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.1

    Secondary: Percentage of Participants With 3 Year OS

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    End point title
    		 Percentage of Participants With 3 Year OS
    End point description
    OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive. For each treatment arm OS rate at 3 years from the date of randomization was determined using the OS times and was estimated using the Kaplan-Meier method. APD included all randomized participants (including the censored participants).
    End point type
    Secondary
    End point timeframe
    Randomization to date of death from any cause assessed at 3 years
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79 [36]
    79 [37]
    79 [38]
    Units: percentage of participants
        number (confidence interval 95%)
    46.7 (34.7 to 57.9)
    40.2 (28.6 to 51.5)
    29.9 (19.1 to 41.3)
    Notes
    [36] - Censored participants: = 41
    [37] - Censored participants: = 37
    [38] - Censored participants: = 33
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified by the number of previous regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of disease (measurable vs. non-measurable).
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stratified by the number of previous regimens (excluding single-agent endocrine therapy) for advanced breast cancer and the status of disease (measurable vs. non-measurable).
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.153
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline till end of follow-up (Up to 6.5 years)
    Adverse event reporting additional description
    All enrolled participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Reporting group description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Reporting group title
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Reporting group description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.

    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Reporting group description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Serious adverse events
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 8 mg/kg Trastuzumab + Standard of Care Chemotherapy 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 78 (30.77%)
    14 / 72 (19.44%)
    15 / 77 (19.48%)
         number of deaths (all causes)
    52
    53
    55
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    chest pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    malaise
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    vaginal haemorrhage
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    epistaxis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    pulmonary embolism
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    depression
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    confusional state
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femur fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hip fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    radiation pneumonitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    cardio-respiratory arrest
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    pericardial effusion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral haemorrhage
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 72 (4.17%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    faecaloma
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct stone
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    jaundice cholestatic
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract obstruction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    osteonecrosis of jaw
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    musculoskeletal pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    cellulitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    clostridium difficile colitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ear infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    fungal infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    influenza
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    meningitis viral
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lymphangitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    soft tissue infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 72 (4.17%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 8 mg/kg Trastuzumab + Standard of Care Chemotherapy 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 78 (97.44%)
    68 / 72 (94.44%)
    75 / 77 (97.40%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    lipoma
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    tumour pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    axillary vein thrombosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    blood pressure fluctuation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    haematoma
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    hot flush
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 72 (2.78%)
    3 / 77 (3.90%)
         occurrences all number
    9
    2
    3
    hypotension
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    1
    hypertension
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 72 (2.78%)
    4 / 77 (5.19%)
         occurrences all number
    4
    2
    6
    lymphoedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    2
    2
    0
    peripheral venous disease
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    vascular pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Surgical and medical procedures
    bladder catheter removal
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    breast reconstruction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    central venous catheterisation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    nail operation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    radiotherapy to brain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    removal of foreign body
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    tooth extraction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    1
    3
    0
    General disorders and administration site conditions
    axillary pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    chest discomfort
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    catheter site pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    catheter site swelling
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    chest pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    2
    1
    2
    complication associated with device
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    chills
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    5
    0
    1
    face oedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    fatigue
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    45 / 78 (57.69%)
    32 / 72 (44.44%)
    41 / 77 (53.25%)
         occurrences all number
    66
    39
    57
    feeling of body temperature change
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    gravitational oedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    gait disturbance
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    generalised oedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    influenza like illness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    6 / 77 (7.79%)
         occurrences all number
    3
    0
    15
    injection site discomfort
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    injection site reaction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 72 (2.78%)
    1 / 77 (1.30%)
         occurrences all number
    4
    2
    1
    malaise
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    3 / 77 (3.90%)
         occurrences all number
    1
    1
    3
    mucosal dryness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    mucosal inflammation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 72 (5.56%)
    3 / 77 (3.90%)
         occurrences all number
    2
    6
    4
    necrosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    7
    1
    1
    oedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    oedema peripheral
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    7 / 72 (9.72%)
    6 / 77 (7.79%)
         occurrences all number
    10
    8
    9
    pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    3
    2
    2
    peripheral swelling
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    pyrexia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    13 / 78 (16.67%)
    11 / 72 (15.28%)
    5 / 77 (6.49%)
         occurrences all number
    18
    17
    8
    swelling face
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    seasonal allergy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    2
    0
    1
    Reproductive system and breast disorders
    breast discharge
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    breast haemorrhage
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    breast pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    2
    cystocele
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    genital rash
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    pelvic pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    vulvovaginal dryness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    vaginal discharge
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    vaginal haemorrhage
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    catarrh
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    cough
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    21 / 78 (26.92%)
    9 / 72 (12.50%)
    12 / 77 (15.58%)
         occurrences all number
    31
    13
    14
    dysphonia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    2
    dyspnoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    15 / 78 (19.23%)
    13 / 72 (18.06%)
    7 / 77 (9.09%)
         occurrences all number
    21
    14
    9
    dyspnoea exertional
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    epistaxis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    6 / 78 (7.69%)
    5 / 72 (6.94%)
    7 / 77 (9.09%)
         occurrences all number
    9
    5
    11
    hypoxia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    laryngeal inflammation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    lung disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    lower respiratory tract congestion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    nasal mucosal disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    nasal inflammation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    nasal dryness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    nasal discomfort
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    nasal discharge discolouration
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    nasal congestion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    4
    1
    0
    oropharyngeal pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 72 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    3
    3
    1
    paranasal sinus hypersecretion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    pleural effusion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    pneumonitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    productive cough
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    2
    pulmonary oedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    pulmonary embolism
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    rhinorrhoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 72 (4.17%)
    3 / 77 (3.90%)
         occurrences all number
    1
    3
    4
    rhinitis allergic
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    9
    1
    1
    sneezing
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    tachypnoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    throat irritation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    wheezing
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    abulia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    anxiety
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 72 (6.94%)
    3 / 77 (3.90%)
         occurrences all number
    2
    6
    3
    confusional state
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    depression
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 78 (8.97%)
    3 / 72 (4.17%)
    3 / 77 (3.90%)
         occurrences all number
    9
    3
    3
    insomnia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 72 (6.94%)
    6 / 77 (7.79%)
         occurrences all number
    4
    5
    9
    libido decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    panic attack
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 78 (8.97%)
    8 / 72 (11.11%)
    6 / 77 (7.79%)
         occurrences all number
    8
    17
    9
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    10 / 78 (12.82%)
    8 / 72 (11.11%)
    7 / 77 (9.09%)
         occurrences all number
    11
    22
    10
    bilirubin conjugated increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 78 (8.97%)
    2 / 72 (2.78%)
    1 / 77 (1.30%)
         occurrences all number
    7
    3
    1
    blood bilirubin decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    blood bilirubin increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 72 (5.56%)
    2 / 77 (2.60%)
         occurrences all number
    5
    8
    2
    blood bilirubin unconjugated increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    blood chloride increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    blood creatinine increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    10 / 78 (12.82%)
    0 / 72 (0.00%)
    11 / 77 (14.29%)
         occurrences all number
    15
    0
    14
    body temperature increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    c-reactive protein increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    cell marker increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    electrocardiogram repolarisation abnormality
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    ejection fraction decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 72 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    4
    1
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    3 / 77 (3.90%)
         occurrences all number
    1
    2
    3
    glomerular filtration rate decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    grip strength decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    hepatic enzyme increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    liver function test abnormal
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    monocyte count decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    monocyte count increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    weight increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    weight decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 72 (2.78%)
    5 / 77 (6.49%)
         occurrences all number
    10
    2
    5
    vitamin d decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    arthropod bite
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    contusion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    fibula fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    fall
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    3 / 77 (3.90%)
         occurrences all number
    4
    1
    4
    femoral neck fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    foreign body
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    hip fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    infusion related reaction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    4
    0
    joint injury
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    procedural pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    radiation skin injury
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    skin abrasion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    spinal compression fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    skin laceration
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    thermal burn
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    thoracic vertebral fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    tooth fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    spinal fracture
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    atrial fibrillation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    atrioventricular block first degree
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    cardiac failure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    2
    cardiomegaly
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    bradycardia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    left atrial enlargement
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    left ventricular dysfunction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    palpitations
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    3
    1
    0
    pericardial effusion
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    sinus tachycardia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    2
    0
    1
    tachycardia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    3
    1
    0
    Nervous system disorders
    balance disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    cerebral thrombosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    dizziness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 72 (4.17%)
    10 / 77 (12.99%)
         occurrences all number
    7
    3
    14
    dysarthria
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    dysgeusia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 72 (2.78%)
    4 / 77 (5.19%)
         occurrences all number
    4
    4
    4
    facial paresis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    headache
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    13 / 78 (16.67%)
    15 / 72 (20.83%)
    11 / 77 (14.29%)
         occurrences all number
    19
    18
    16
    hemiparesis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    lethargy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    3
    2
    0
    loss of consciousness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    memory impairment
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    migraine
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    nerve compression
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    neuropathy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    15 / 72 (20.83%)
    7 / 77 (9.09%)
         occurrences all number
    5
    20
    8
    peripheral motor neuropathy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    3
    psychomotor skills impaired
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    presyncope
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    radiculopathy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    seizure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    sinus headache
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    spinal cord compression
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    somnolence
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    stupor
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    syncope
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    taste disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    2
    3
    0
    tension headache
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    tremor
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    3
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    30 / 78 (38.46%)
    16 / 72 (22.22%)
    20 / 77 (25.97%)
         occurrences all number
    47
    19
    25
    anaemia macrocytic
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    febrile neutropenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 72 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    3
    0
    iron deficiency anaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    leukocytosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    leukopenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    18 / 78 (23.08%)
    10 / 72 (13.89%)
    9 / 77 (11.69%)
         occurrences all number
    27
    58
    13
    lymphocytosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    lymphopenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 72 (5.56%)
    4 / 77 (5.19%)
         occurrences all number
    7
    16
    5
    neutropenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    38 / 78 (48.72%)
    26 / 72 (36.11%)
    27 / 77 (35.06%)
         occurrences all number
    72
    88
    59
    neutrophilia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    thrombocytopenia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    23 / 78 (29.49%)
    5 / 72 (6.94%)
    23 / 77 (29.87%)
         occurrences all number
    33
    20
    42
    Ear and labyrinth disorders
    deafness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    ear pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    4
    2
    0
    middle ear inflammation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    otorrhoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    vertigo
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    2 / 77 (2.60%)
         occurrences all number
    1
    2
    2
    Eye disorders
    blepharitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    blindness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    cataract
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    cataract nuclear
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    conjunctival hyperaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    conjunctival irritation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    conjunctivitis allergic
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    diplopia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    2
    0
    1
    dry eye
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    3 / 77 (3.90%)
         occurrences all number
    4
    2
    3
    eye discharge
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    eye disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    eye irritation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    eye pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    1
    2
    0
    eye pruritus
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    intraocular haematoma
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    lacrimation increased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 78 (8.97%)
    2 / 72 (2.78%)
    5 / 77 (6.49%)
         occurrences all number
    8
    2
    5
    ocular hyperaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    periorbital oedema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    vision blurred
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 72 (1.39%)
    3 / 77 (3.90%)
         occurrences all number
    4
    1
    3
    visual acuity reduced
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    visual impairment
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    xerophthalmia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 72 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    9
    0
    3
    abdominal pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    24 / 78 (30.77%)
    16 / 72 (22.22%)
    19 / 77 (24.68%)
         occurrences all number
    35
    20
    26
    anal incontinence
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    anorectal discomfort
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    aphthous ulcer
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    1 / 77 (1.30%)
         occurrences all number
    0
    2
    1
    ascites
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    1 / 77 (1.30%)
         occurrences all number
    0
    2
    1
    abdominal rigidity
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    defaecation urgency
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    colitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    constipation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    11 / 78 (14.10%)
    15 / 72 (20.83%)
    8 / 77 (10.39%)
         occurrences all number
    13
    19
    9
    diarrhoea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    62 / 78 (79.49%)
    18 / 72 (25.00%)
    60 / 77 (77.92%)
         occurrences all number
    169
    33
    163
    dry mouth
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 72 (5.56%)
    5 / 77 (6.49%)
         occurrences all number
    5
    7
    6
    dyspepsia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    8 / 78 (10.26%)
    6 / 72 (8.33%)
    7 / 77 (9.09%)
         occurrences all number
    15
    8
    8
    dysphagia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    enterocolitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    gastric ulcer
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    gastritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    5
    1
    1
    gastrointestinal disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    gastrointestinal toxicity
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    5
    1
    1
    gingival bleeding
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    3
    gingival pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    glossodynia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    flatulence
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    haemorrhoidal haemorrhage
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    haemorrhoids
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    haematochezia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    ileus
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    lip swelling
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    mouth ulceration
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    6
    2
    0
    nausea
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    38 / 78 (48.72%)
    26 / 72 (36.11%)
    32 / 77 (41.56%)
         occurrences all number
    56
    36
    48
    oral dysaesthesia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    oesophageal pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    pancreatitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    proctalgia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    rectal haemorrhage
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    toothache
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    2
    stomatitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    8 / 72 (11.11%)
    7 / 77 (9.09%)
         occurrences all number
    4
    13
    9
    vomiting
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    22 / 78 (28.21%)
    11 / 72 (15.28%)
    22 / 77 (28.57%)
         occurrences all number
    33
    13
    27
    Hepatobiliary disorders
    cholestasis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    hepatic cytolysis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    hepatotoxicity
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    jaundice
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    portal vein thrombosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    pseudocirrhosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    acne
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    alopecia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    8 / 78 (10.26%)
    8 / 72 (11.11%)
    7 / 77 (9.09%)
         occurrences all number
    9
    8
    8
    blister
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    cutaneous lupus erythematosus
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    dermatitis acneiform
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    dermatitis allergic
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    dermatitis contact
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    dry skin
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 72 (5.56%)
    4 / 77 (5.19%)
         occurrences all number
    5
    4
    4
    eczema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    3
    0
    2
    erythema
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 72 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    3
    2
    hyperhidrosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    intertrigo
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    nail dystrophy
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    nail disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    4 / 77 (5.19%)
         occurrences all number
    2
    1
    4
    nail discolouration
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    nail bed disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    nail ridging
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    night sweats
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    onychomadesis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    2
    onycholysis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    onychoclasis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    4
    0
    1
    pain of skin
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    3
    0
    4
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    13 / 72 (18.06%)
    1 / 77 (1.30%)
         occurrences all number
    0
    20
    2
    papule
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    photosensitivity reaction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    petechiae
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    prurigo
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    pruritus
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    12 / 78 (15.38%)
    3 / 72 (4.17%)
    9 / 77 (11.69%)
         occurrences all number
    17
    3
    9
    purpura
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    rash
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    15 / 78 (19.23%)
    9 / 72 (12.50%)
    14 / 77 (18.18%)
         occurrences all number
    19
    13
    20
    sensitive skin
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    skin discolouration
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    skin ulcer
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    skin reaction
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    skin irritation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    skin fissures
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    0
    4
    0
    skin exfoliation
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    skin disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    stasis dermatitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    urticaria
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    0
    0
    4
    xeroderma
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    8
    bladder disorder
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    bladder pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    bladder tamponade
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    chronic kidney disease
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    cystitis noninfective
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    2
    dysuria
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    haematuria
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    1
    2
    0
    incontinence
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    nephropathy toxic
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    nephrolithiasis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    pollakiuria
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    3
    polyuria
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    renal failure
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    1
    urinary incontinence
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    urinary retention
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    14 / 78 (17.95%)
    11 / 72 (15.28%)
    12 / 77 (15.58%)
         occurrences all number
    21
    16
    14
    arthritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    2
    1
    bone pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    7 / 72 (9.72%)
    3 / 77 (3.90%)
         occurrences all number
    1
    10
    3
    back pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 72 (8.33%)
    12 / 77 (15.58%)
         occurrences all number
    11
    8
    14
    costochondritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    flank pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    1
    haematoma muscle
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    inguinal mass
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    joint range of motion decreased
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    limb discomfort
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    muscle spasms
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 72 (2.78%)
    3 / 77 (3.90%)
         occurrences all number
    5
    2
    3
    myalgia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 78 (8.97%)
    10 / 72 (13.89%)
    7 / 77 (9.09%)
         occurrences all number
    9
    11
    8
    musculoskeletal pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    1
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    1 / 77 (1.30%)
         occurrences all number
    1
    2
    1
    muscular weakness
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    1
    muscle twitching
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    neck pain
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 72 (2.78%)
    3 / 77 (3.90%)
         occurrences all number
    1
    2
    4
    osteonecrosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    osteoporosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    pain in extremity
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    8 / 72 (11.11%)
    5 / 77 (6.49%)
         occurrences all number
    4
    11
    6
    pain in jaw
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    osteonecrosis of jaw
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    2
    0
    1
    plantar fasciitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    covid-19
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    bronchitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    candida infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    catheter site infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    cellulitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    0
    2
    0
    conjunctivitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    2
    1
    2
    device related infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    ear infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    folliculitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    fungal skin infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    gastroenteritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 72 (5.56%)
    0 / 77 (0.00%)
         occurrences all number
    5
    5
    0
    gastroenteritis norovirus
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    herpes zoster
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    infected bite
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    infected dermal cyst
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    influenza
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 72 (2.78%)
    5 / 77 (6.49%)
         occurrences all number
    6
    2
    5
    kidney infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    lip infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    2
    lymphangitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    5
    0
    0
    localised infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    nail infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 72 (2.78%)
    3 / 77 (3.90%)
         occurrences all number
    5
    2
    3
    oral infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    oral candidiasis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    onychomycosis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    paronychia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    pharyngotonsillitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    pharyngitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    3
    1
    2
    pneumonia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    3
    1
    2
    postoperative wound infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    pyelonephritis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    sepsis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    rhinitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    4
    1
    2
    respiratory tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    rash pustular
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    spinal cord infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    sinusitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    2
    skin infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    tooth abscess
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    tooth infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    12 / 78 (15.38%)
    8 / 72 (11.11%)
    4 / 77 (5.19%)
         occurrences all number
    19
    12
    5
    urinary tract infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    8 / 78 (10.26%)
    6 / 72 (8.33%)
    10 / 77 (12.99%)
         occurrences all number
    16
    9
    24
    vaginal infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    1
    vascular device infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    viral infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    3
    0
    1
    viral sinusitis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    vulvovaginal candidiasis
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    wound infection
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    19 / 78 (24.36%)
    13 / 72 (18.06%)
    16 / 77 (20.78%)
         occurrences all number
    26
    15
    20
    dehydration
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 72 (5.56%)
    2 / 77 (2.60%)
         occurrences all number
    3
    4
    2
    hypernatraemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    4
    0
    hypercalcaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    1
    hyperchloraemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    3
    0
    hypercholesterolaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    hyperglycaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 72 (5.56%)
    1 / 77 (1.30%)
         occurrences all number
    1
    9
    3
    hyperkalaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 72 (1.39%)
    3 / 77 (3.90%)
         occurrences all number
    6
    1
    3
    hyperuricaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 72 (2.78%)
    0 / 77 (0.00%)
         occurrences all number
    0
    4
    0
    hypoalbuminaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 72 (2.78%)
    2 / 77 (2.60%)
         occurrences all number
    2
    2
    2
    hypocalcaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 72 (5.56%)
    2 / 77 (2.60%)
         occurrences all number
    1
    5
    2
    hypoglycaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    hypokalaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    7 / 78 (8.97%)
    4 / 72 (5.56%)
    7 / 77 (9.09%)
         occurrences all number
    18
    5
    14
    hypomagnesaemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    2
    hyponatraemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 72 (1.39%)
    2 / 77 (2.60%)
         occurrences all number
    3
    1
    3
    hypophosphataemia
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    iron deficiency
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 72 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    vitamin b12 deficiency
    alternative dictionary used: MedDRA 27.0
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 72 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2015
    - Added the safety lead-in portion for Arm A due to no data around the triplet combination
    23 Jan 2019
    - Updated the safety language regarding hepatic monitoring, assessment of renal function, and venous thromboembolic events (VTEs) for ongoing patients and align with the updated label of abemaciclib.
    10 Feb 2020
    - Added dose modification table for interstitial lung disease (ILD)/pneumonitis and updated guidance for management of ILD/pneumonitis.

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

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