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    Clinical Trial Results:
    A Randomized, Multicenter, Double Blind Phase 3 Study of PD 0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole for the Treatment of Postmenopausal Women With ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti-Cancer Treatment for Advanced Disease

    Summary
    EudraCT number
    		 2012-004601-27
    Trial protocol
    		 DE   BE   IE   FR   GB   ES   HU   IT   PL  
    Global end of trial date
    09 Nov 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Nov 2024
    First version publication date
    16 Dec 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A5481008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01740427
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 May 2024
    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
    To demonstrate that the combination of PD-0332991 with letrozole was superior to placebo plus letrozole in prolonging progression-free survival (PFS) in postmenopausal women with estrogen receptor (ER)-positive/ human epidermal growth factor receptor 2 (HER2)-negative ER (+)/HER2 (-) advanced breast cancer (ABC) who had not received any prior systemic anti-cancer therapies for their advanced/metastatic disease.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines . In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of study participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Feb 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 46 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    Canada: 70
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Ireland: 22
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Japan: 46
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 24
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 197
    Worldwide total number of subjects
    666
    EEA total number of subjects
    190
    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)
    404
    From 65 to 84 years
    255
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 666 participants were randomised at 239 centers in 19 countries.

    Pre-assignment
    Screening details
    		 The study consisted of a screening visit within 28 days before randomization, an active treatment phase, divided in cycles of 28 days each, and a post-treatment follow-up period during which survival and new anti-cancer therapy information was collected every 6 months (+/-7 days) from the last dose of study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Palbociclib Plus Letrozole
    Arm description
    		 Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg orally, QD.

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    125 mg orally, QD for 21 days.

    Arm title
    		 Placebo Plus Letrozole
    Arm description
    		 Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg orally, QD.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Orally, QD for 21 days.

    Number of subjects in period 1
    		Palbociclib Plus Letrozole Placebo Plus Letrozole
    Started
    444
    222
    Completed
    0
    0
    Not completed
    444
    222
         Adverse event, serious fatal
    10
    3
         Objective Progression or Relapse
    286
    172
         Adverse event, non-fatal
    32
    9
         Participant Refused Continued Treatment
    27
    15
         Site Terminated by Sponsor
    1
    -
         Lost to follow-up
    3
    -
         Global Deterioration of Health Status
    28
    12
         Unspecified reasons
    52
    8
         Protocol deviation
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palbociclib Plus Letrozole
    Reporting group description
    		 Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group title
    Placebo Plus Letrozole
    Reporting group description
    		 Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole Total
    Number of subjects
    		 444 222 666
    Age categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 263 141 404
        From 65-84 years
    		 176 79 255
        85 years and over
    		 5 2 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ( 10.6 ) 60.6 ( 11.2 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 444 222 666
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Palbociclib Plus Letrozole
    Reporting group description
    		 Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group title
    Placebo Plus Letrozole
    Reporting group description
    		 Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Primary: Progression-Free Survival (PFS) as Assessed by the Investigator

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    End point title
    		 Progression-Free Survival (PFS) as Assessed by the Investigator
    End point description
    PFS=time from date of randomisation to date of 1st documentation of objective tumor progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)/death in absence of progressive disease(PD).If tumor progression data include more than 1 date,1st date will be used.PFS=(1st event date−randomisation date+1)/30.4.Progression=using RECIST v1.1,20% increase in sum of diameters of target measurable lesions above smallest sum observed(over baseline if no decrease in sum is observed during therapy),with minimum absolute increase of 5mm,unequivocal progression of pre-existing non-target lesions,appearance of new lesions.Intent to treat(ITT)population/full analysis set:randomised participants,with drug assignment designated according to initial randomisation,regardless whether participants received medication/received different drug from that to which they were randomised.99999=value was not available as there wasn’t enough PD events in treatment group at time of analysis.
    End point type
    Primary
    End point timeframe
    From randomisation date to date of first documentation of progression OR death (up to approximately 2.5 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Months
        median (confidence interval 95%)
    24.8 (22.1 to 99999)
    14.5 (12.9 to 17.1)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [1]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.576
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.463
         upper limit
    		 0.718
    Notes
    [1] - 1-sided p-value from the stratified log-rank test.

    Secondary: Objective Response as Assessed by the Investigator

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    End point title
    		 Objective Response as Assessed by the Investigator
    End point description
    OR defined as overall complete response (CR)/partial response (PR) according to RECIST v1.1. Objective Response Rate (ORR) is defined as proportion of participants with CR/PR relative to all randomised participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment, or who died, progressed/ dropped out for any reason prior to reaching CR/PR were counted as non-responders in assessment of ORR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: >=30% decrease under baseline of sum of diameters of all target measurable lesions. Short diameter is used in sum for target nodes, while longest diameter is used in sum for all other target lesions. Stable Disease: neither sufficient shrinkage nor increase to qualify for disease progression. ITT population or full analysis set was analysed.
    End point type
    Secondary
    End point timeframe
    From randomisation until end of treatment (up to approximately 2.5 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percentage of participants
        number (confidence interval 95%)
    46.4 (41.7 to 51.2)
    38.3 (31.9 to 45.0)
    Statistical analysis title
    		 Palbociclib +Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Stratified analysis: Stratified by disease site (visceral vs non-visceral) per randomization.
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0224 [2]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.428
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.008
         upper limit
    		 2.03
    Notes
    [2] - 1-sided p-value is from exact test.

    Secondary: Objective Response: Participants With Measurable Disease at Baseline as Assessed by the Investigator

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    End point title
    		 Objective Response: Participants With Measurable Disease at Baseline as Assessed by the Investigator
    End point description
    OR is defined as overall CR or PR according to RECIST v1.1. ORR is defined as proportion of participants with CR or PR relative to all randomised participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment, or who died, progressed/ dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in sum for target nodes, while the longest diameter is used in the sum for all other target lesions. Stable Disease (SD): neither sufficient shrinkage nor increase to qualify for disease progression. ITT population or full analysis set was analysed.
    End point type
    Secondary
    End point timeframe
    From randomisation until end of treatment (up to approximately 2.5 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    338
    171
    Units: Percentage of participants
        number (confidence interval 95%)
    60.7 (55.2 to 65.9)
    49.1 (41.4 to 56.9)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Stratified analysis: Stratified by disease site (visceral vs non-visceral) per randomization.
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.009 [3]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.594
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 2.347
    Notes
    [3] - 1-sided p-value is from exact test.

    Secondary: Disease Control (DC)/Clinical Benefit Response (CBR)

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    End point title
    		 Disease Control (DC)/Clinical Benefit Response (CBR)
    End point description
    DC = overall CR, PR, stable disease (SD) >=24 weeks according to RECIST version 1.1. Disease Control Rate (DCR) = participants with CR, PR, or SD >=24 weeks relative to all randomised participants. Participants who don’t have on-study radiographic tumor reevaluation, who received anti-tumor treatment, best response of SD >= 24 weeks, who died, progressed, dropped out for any reason prior to achieving reaching CR/PR and best response of SD >= 24 weeks was counted as non-responders in DCR. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: >=30% decrease under baseline of sum of diameters of all target measurable lesions. Short diameter is used in sum for target nodes, while longest diameter is used in sum for all other target lesions. SD: neither sufficient shrinkage nor increase to qualify for disease progression. ITT population or full analysis set was analysed.
    End point type
    Secondary
    End point timeframe
    From randomisation until end of treatment (up to approximately 2.5 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percentage of participants
        number (confidence interval 95%)
    85.8 (82.2 to 88.9)
    71.2 (64.7 to 77.0)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Stratified analysis: Stratified by disease site (visceral, non-visceral) per randomization.
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [4]
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.451
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.619
         upper limit
    		 3.722
    Notes
    [4] - 1-sided p-value is from exact test.

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    DR is defined as time from first documentation of objective tumor response (CR or PR) to first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, first date will be used. DR was calculated as [date response ended (i.e. date of PD or death) – first CR or PR date + 1)]/30.4. DR would only be calculated for the subgroup of participants with an objective tumor response. Per RECIST v1.1, CR: Complete disappearance of target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10mm). PR: >=30% decrease under baseline of sum of diameters of all target measurable lesions. Short diameter is used in sum for target nodes, while longest diameter is used in sum for all other target lesions. Stable Disease (SD): neither sufficient shrinkage nor increase to qualify for disease progression. ITT population or full analysis set was analysed.
    End point type
    Secondary
    End point timeframe
    From randomisation until end of treatment (up to approximately 2.5 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    206
    85
    Units: Months
        median (confidence interval 95%)
    20.1 (19.3 to 28.0)
    16.7 (13.8 to 22.5)
    No statistical analyses for this end point

    Secondary: PFS by Tumor tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6)

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    End point title
    		 PFS by Tumor tissue Biomarkers Status, Including Genes (eg, Copy Numbers of CCND1, CDKN2A), Proteins (eg, Ki67, pRb), and RNA Expression (eg, cdk4, cdk6)
    End point description
    PFS by biomarker status by Investigator assessment. Progression by RECIST v1.1 = 20% increase in sum of longest diameter of target lesions, or measurable increase in non-target lesion, or appearance of new lesions. Positive = H-Score >=1 and negative = H-Score <1. H-Score was calculated as sum of the % of cells at each level of staining intensity (0, 1+, 2+, and 3+) multiplied by staining intensity value: H-Score = (% at 0)*0 + (% at 1+)*1 + (% at 2+)*2 + (% at 3+)*3. H-Score values range from 0 to 300. ER stands for estrogen receptor and Rb stands for retinoblastoma susceptibility gene product. ITT population or full analysis set included all participants who were randomised, with study medication, regardless of whether participants received study medication or received a different drug from that to which they were randomised. Here "Number Analysed (n)" signifies number of participants evaluable for specified rows. 99999 indicates insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From randomisation until end of treatment (up to approximately 24 Months)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Months
    median (confidence interval 95%)
        ER Positive (n=338, 166)
    24.9 (22.2 to 99999)
    16.3 (12.9 to 19.1)
        ER Negative (n=40, 22)
    15.6 (8.3 to 22.0)
    5.4 (2.7 to 11.1)
        Rb Positive (n=345, 167)
    24.2 (21.4 to 25.7)
    13.7 (11.0 to 16.5)
        Rb Negative (n=29, 22)
    99999 (11.4 to 99999)
    18.5 (2.9 to 99999)
        Cyclin D1 Positive (n=370, 179)
    24.8 (21.5 to 27.6)
    13.8 (11.3 to 16.8)
        Cyclin D1 Negative (n=5, 10)
    11.1 (2.2 to 23.9)
    8.1 (0.4 to 99999)
        p16 Positive (n=305, 161)
    24.8 (21.5 to 99999)
    13.8 (11.1 to 16.8)
        p16 Negative (n=59, 25)
    16.8 (11.1 to 24.9)
    13.8 (8.1 to 99999)
        p16 H-Score<175 (n=341, 177)
    23.7 (19.6 to 25.7)
    13.8 (11.2 to 16.8)
        p16 H-Score >=175 (n=23, 9)
    24.2 (11.1 to 99999)
    5.6 (1.5 to 19.1)
        Ki67 <= 20% (n=216, 102)
    27.6 (24.2 to 99999)
    16.8 (13.7 to 22.0)
        Ki67 >20% (n=152, 83)
    17.5 (13.8 to 22.0)
    8.4 (5.6 to 13.6)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for ER positive
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.571
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.443
         upper limit
    		 0.737
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for ER Negative
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.003
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.405
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.218
         upper limit
    		 0.751
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for Rb Positive
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.531
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.416
         upper limit
    		 0.68
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for Rb Negative
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3237
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.675
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.308
         upper limit
    		 1.481
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for Cyclin D1 Positive
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.555
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.437
         upper limit
    		 0.705
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for Cyclin D1 Negative
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9964
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.997
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.287
         upper limit
    		 3.461
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for p16 Positive
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.518
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.67
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for p16 Negative
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3221
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.731
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.392
         upper limit
    		 1.364
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for p16 HScore<175
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.581
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.455
         upper limit
    		 0.742
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for p16 HScore>=175
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0022
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.255
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.65
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for Ki67 <= 20%
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.379
         upper limit
    		 0.742
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for Ki67 >20%
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0007
    Method
    		 Unstratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.569
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.409
         upper limit
    		 0.791

    Secondary: Corrected QT interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14

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    End point title
    		 Corrected QT interval (QTc) Time-Matched Change From Baseline on Cycle 1 Day 14
    End point description
    Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The average was calculated. The time corresponding to beginning of depolarisation to repolarisation of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Time-matched change from baseline values were reported for QTc analysis population. QTc analysis set is a subset of as treated (AT) population who were in Group 1; their QTc was used to study the effect of palbociclib on QT interval via serial triplicate ECGs with PK draws; and who had >= 1 pair of time-matched Day 0 and palbociclib postdose (Cycle1 Day 14) measurements.
    End point type
    Secondary
    End point timeframe
    Time-matched triplicate ECGs were collected at 0 (predose), 2, 4, 6 and 8 hours on Day 0 and on Cycle1 Day 14
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    76
    47
    Units: Millisecond (msec)
    least squares mean (confidence interval 90%)
        QTcS at 0 hour
    0.80 (-1.67 to 3.26)
    2.95 (-0.19 to 6.10)
        QTcS at 2 hour
    3.32 (0.79 to 5.85)
    1.65 (-1.48 to 4.78)
        QTcS at 4 hour
    2.76 (0.23 to 5.30)
    1.74 (-1.39 to 4.87)
        QTcS at 6 hour
    4.49 (1.96 to 7.02)
    0.72 (-2.41 to 3.85)
        QTcS at 8 hour
    0.94 (-1.60 to 3.48)
    3.14 (0.01 to 6.27)
        QTcF at 0 hour
    1.10 (-1.39 to 3.58)
    3.06 (-0.11 to 6.23)
        QTcF at 2 hour
    3.68 (1.12 to 6.23)
    1.73 (-1.43 to 4.88)
        QTcF at 4 hour
    2.86 (0.31 to 5.41)
    1.54 (-1.62 to 4.70)
        QTcF at 6 hour
    4.57 (2.01 to 7.12)
    0.71 (-2.44 to 3.87)
        QTcF at 8 hour
    1.21 (-1.36 to 3.77)
    2.84 (-0.31 to 6.00)
        QTcB at 0 hour
    -0.11 (-2.83 to 2.61)
    2.78 (-0.69 to 6.25)
        QTcB at 2 hour
    1.46 (-1.34 to 4.25)
    0.83 (-2.63 to 4.28)
        QTcB at 4 hour
    2.58 (-0.22 to 5.38)
    2.47 (-0.98 to 5.92)
        QTcB at 6 hour
    4.03 (1.24 to 6.83)
    0.53 (-2.92 to 3.99)
        QTcB at 8 hour
    -0.17 (-2.98 to 2.64)
    4.14 (0.69 to 7.59)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Corrected QT interval (QTc)

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    End point title
    		 Percentage of Participants With Corrected QT interval (QTc)
    End point description
    Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Percentage of participants with post-baseline maximum absolute values and maximum increase from baseline were summarized for the safety analysis population. The as-treated (AT) population or safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    For safety monitoring triplicate ECGs were obtained at 0 hour (pre-dose) on Day 1 of Cycle 1, Day 14 of Cycles 1 and Cycle 2, then on Day 1 of Cycles 4, 7, and 10 (ECGs beyond Cycle 10 were performed as clinically indicated)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    441
    220
    Units: Percentage of participants
    number (not applicable)
        Maximum QTcS <450 msec
    80.5
    85.9
        Maximum QTcS 450-<480 msec
    17.9
    11.8
        Maximum QTcS 480-<500 msec
    1.1
    2.3
        Maximum QTcS >=500 msec
    0.5
    0
        Maximum QTcF <450 msec
    85.9
    89.5
        Maximum QTcF 450-<480 msec
    12.2
    9.5
        Maximum QTcF 480-<500 msec
    1.6
    0.9
        Maximum QTcF >=500 msec
    0.2
    0
        Maximum QTcB <450 msec
    64.9
    69.1
        Maximum QTcB 450-<480 msec
    32.2
    27.3
        Maximum QTcB 480-<500 msec
    2.3
    3.2
        Maximum QTcB >=500 msec
    0.7
    0.5
        Maximum QTcS Change <30 msec
    92.7
    94.5
        Maximum QTcS 30<=Change <60 msec
    6.6
    5.5
        Maximum QTcS Change>=60 msec
    0.7
    0
        Maximum QTcF Change <30 msec
    91.6
    93.6
        Maximum QTcF 30≤Change <60 msec
    7.9
    6.4
        Maximum QTcF Change>=60 msec
    0.5
    0
        Maximum QTcB Change <30 msec
    88.9
    91.4
        Maximum QTcB 30<=Change <60 msec
    10.2
    8.2
        Maximum QTcB Change>=60 msec
    0.9
    0.5
    No statistical analyses for this end point

    Secondary: Change from Baseline Between Treatment Comparison in Functional Assessment of Cancer therapy -Breast (FACT-B)

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    End point title
    		 Change from Baseline Between Treatment Comparison in Functional Assessment of Cancer therapy -Breast (FACT-B)
    End point description
    FACT is modular approach to assess participant health-related quality of life using ‘core’ set of questions (FACT-G) as well as cancer site-specific module. FACT-G is 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. FACT-B consisted of FACT-G (27-item) and breast-specific module: 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to five-level scale where 0=not at all, 1=little bit, 2=somewhat, 3=quite a bit, and 4=very much. FACT-B total score = Physical Well-Being + Social/Family Well-Being + Emotional Well-Being + Functional Well-Being + Breast Cancer Subscale. As each item ranges from 0-4, the range of possible scores is 0-144, with 0=worst possible score and 144=best. PRO Analysis Set is subset of ITT participants, who had both baseline and at least one follow-up PRO assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 2.5 years
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    439
    218
    Units: Units on a scale
        arithmetic mean (confidence interval 95%)
    -0.106 (-1.42 to 1.21)
    0.219 (-1.68 to 2.12)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7822
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.325
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.63
         upper limit
    		 1.98

    Secondary: Change from Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index

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    End point title
    		 Change from Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index
    End point description
    The EuroQol EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 descriptors are summarised to create a single summary score. An overall utility score is calculated based on these domains, with a range score from 0 (worse health scenario) to a maximum of 1.0 (best health scenario). Patient Reported Outcome (PRO) Analysis Set was a subset of ITT participants, who had both baseline and at least one follow-up PRO assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 2.5 years
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    437
    218
    Units: Units on a scale
        arithmetic mean (confidence interval 95%)
    0.014 (0.00 to 0.03)
    -0.010 (-0.03 to 0.01)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0925
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.023
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0.051

    Secondary: Observed Plasma Trough Concentration (Ctrough) at Steady-State

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    End point title
    		 Observed Plasma Trough Concentration (Ctrough) at Steady-State [5]
    End point description
    Summary of plasma palbociclib within-participant mean steady-state trough concentrations. Pharmacokinetic analysis set was a subset of AT participants, who were treated with Palbociclib and had at least one measured plasma concentration. Here "number of participants analysed (n)" signifies number of participants evaluable for specified rows.
    End point type
    Secondary
    End point timeframe
    0 hour (predose) on Day 14 of cycles 1 and 2
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was summarized for specified reporting arms only.
    End point values
    		 Palbociclib Plus Letrozole
    Number of subjects analysed
    423
    Units: Nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 14 (n=395)
    70.1 ( 59 )
        Cycle 2 Day 14 (n=401)
    64.2 ( 82 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities

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    End point title
    		 Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs): All Causalities
    End point description
    AE:any untoward medical occurrence in clinical investigation participant administered product/medical device;event need not necessarily have causal relationship with treatment/usage.SAE:any untoward medical occurrence at any dose resulted in death;life-threatening;required hospitalisation;resulted in persistent/significant disability/congenital anomaly/birth defect.TEAE:events that occurred between first dose of study drug up to 28 days after last dose that were absent before treatment/that worsened relative to pretreatment state.Severity was graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE),Version 4.0 as Grade 1=mild,Grade 2=moderate,Grade 3=severe,Grade 4=life-threatening,Grade 5=death related to AE.Discontinuation included permanent,temporary discontinuation and dose reduction due to AEs.AT population=participants who received 1 dose of study medication,with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 28 days after last dose of study drug (final analysis till study completion, approximately up to 10.51 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percentage of participants
    number (not applicable)
        Participants with AEs
    99.1
    96.4
        Participants with SAEs
    28.2
    17.1
        Participants with Grade 3 or 4 AEs
    83.1
    30.2
        Participants with Grade 5 AEs
    3.6
    2.3
        Permanently discontinued study due to AEs
    4.1
    2.3
        Permanently disc. palbociclib/placebo due to AEs
    14.4
    6.3
        Permanently discontinued letrozole due to AEs
    9.2
    5.9
        Temporarily disc. palbociclib/placebo due to AEs
    79.7
    17.1
        Temporarily discontinued letrozole due to AEs
    23.0
    11.3
        With palbociclib/placebo dose reduction due to AEs
    41.9
    2.3
    No statistical analyses for this end point

    Secondary: Overall Survival (OS): Primary Analysis

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    End point title
    		 Overall Survival (OS): Primary Analysis
    End point description
    OS was defined as the time from date of randomisation to date of death due to any cause. Participants without survival data beyond the date of their last follow-up were censored on the last date they were known to be alive. Data for this endpoint was reported at primary analysis. ITT population or full analysis set included all participants who were randomised, with study medication, regardless of whether participants received study medication or received a different drug from that to which they were randomised.
    End point type
    Secondary
    End point timeframe
    From date of randomisation until death due to any cause or censored (assessed up to data cut-off date of 15-Nov-2021, approximately 8.7 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Months
        median (confidence interval 95%)
    53.9 (49.8 to 60.8)
    51.2 (43.7 to 58.9)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.33775 [6]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.956
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.777
         upper limit
    		 1.177
    Notes
    [6] - 1-sided p-value from the stratified log-rank test.

    Secondary: Overall Survival (OS): Final Analysis

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    End point title
    		 Overall Survival (OS): Final Analysis
    End point description
    OS was defined as the time from date of randomisation to date of death due to any cause. Participants without survival data beyond the date of their last follow-up were censored on the last date they were known to be alive. Data for this endpoint was reported at final analysis. ITT population or full analysis set included all participants who were randomised, with study medication, regardless of whether participants received study medication or received a different drug from that to which they were randomised.
    End point type
    Secondary
    End point timeframe
    From date of randomisation until death due to any cause or censored (final analysis till study completion, approximately up to 10.51 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Months
        median (confidence interval 95%)
    53.8 (49.8 to 59.2)
    49.8 (42.3 to 56.4)
    Statistical analysis title
    		 Palbociclib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Palbociclib Plus Letrozole v Placebo Plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.208706 [7]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.921
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.755
         upper limit
    		 1.124
    Notes
    [7] - 1-sided p-value from the stratified log-rank test.

    Secondary: Survival Probability at 1 Year, 2 Year and 3 Year

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    End point title
    		 Survival Probability at 1 Year, 2 Year and 3 Year
    End point description
    One, two or three-year survival probability was defined as the probability of survival 1 year, 2 or 3 years after the date of randomisation. The survival probability was estimated using the Kaplan-Meier method and 2-sided 95% confidence interval (CI) was calculated using the product limit method. ITT population or full analysis set included all participants who were randomised, with study medication, regardless of whether participants received study medication or received a different drug from that to which they were randomised.
    End point type
    Secondary
    End point timeframe
    1, 2 and 3 years after randomisation
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percent probability
    number (confidence interval 95%)
        1 year survival probability
    92.7 (89.8 to 94.7)
    94.9 (91.0 to 97.2)
        2 year survival probability
    78.4 (74.1 to 82.0)
    82.5 (76.6 to 87.0)
        3 year survival probability
    69.8 (65.1 to 73.9)
    65.0 (58.0 to 71.1)
    No statistical analyses for this end point

    Secondary: Number of Participants with Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade

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    End point title
    		 Number of Participants with Laboratory Abnormalities by Maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade
    End point description
    Laboratory abnormalities included anemia, hemoglobin increased, neutrophils (absolute), platelets, white blood cells, alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), bilirubin (total), creatinine, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormalities were graded by CTCAE version (v) 4.0 as Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe and Grade 4 = life-threatening. Categories with at least 1 non-zero data values were reported. AT population included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received. Here, “Number of Participants Analysed” signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 28 days after last dose of study drug (assessed up to analysis date of 15-Nov-2021, approximately 8.7 years)
    End point values
    		 Palbociclib Plus Letrozole Placebo Plus Letrozole
    Number of subjects analysed
    444
    221
    Units: Participants
        Anemia: Grade 1-2
    328
    90
        Anemia: Grade 3
    30
    6
        Hemoglobin Increased: Grade 1-2
    14
    25
        Hemoglobin Increased: Grade 3
    1
    0
        Neutrophils (Absolute): Grade 1-2
    109
    42
        Neutrophils (Absolute): Grade 3
    254
    2
        Neutrophils (Absolute): Grade 4
    60
    1
        Platelets: Grade 1-2
    289
    32
        Platelets: Grade 3
    6
    0
        Platelets: Grade 4
    1
    0
        White Blood Cells: Grade 1-2
    248
    57
        White Blood Cells: Grade 3
    177
    0
        White Blood Cells: Grade 4
    6
    0
        ALT: Grade 1-2
    222
    76
        ALT: Grade 3
    16
    0
        ALT: Grade 4
    1
    0
        Alkaline Phosphatase: Grade 1-2
    174
    95
        Alkaline Phosphatase: Grade 3
    7
    0
        AST: Grade 1-2
    260
    82
        AST: Grade 3
    23
    2
        Bilirubin (Total): Grade 1-2
    33
    11
        Bilirubin (Total): Grade 3
    3
    0
        Creatinine: Grade 1-2
    418
    201
        Creatinine: Grade 3
    8
    0
        Creatinine: Grade 4
    2
    0
        Hypercalcemia: Grade 1-2
    111
    54
        Hypercalcemia: Grade 3
    1
    2
        Hyperkalemia: Grade 1-2
    118
    51
        Hyperkalemia: Grade 3
    6
    1
        Hyperkalemia: Grade 4
    2
    0
        Hypermagnesemia: Grade 1-2
    71
    26
        Hypermagnesemia: Grade 3
    9
    6
        Hypermagnesemia: Grade 4
    2
    0
        Hypernatremia: Grade 1-2
    94
    35
        Hypernatremia: Grade 3
    8
    1
        Hypoalbuminemia: Grade 1-2
    118
    42
        Hypoalbuminemia: Grade 3
    2
    0
        Hypocalcemia: Grade 1-2
    158
    48
        Hypocalcemia: Grade 3
    4
    1
        Hypocalcemia: Grade 4
    3
    0
        Hypokalemia: Grade 1-2
    105
    32
        Hypokalemia: Grade 3
    11
    2
        Hypomagnesemia: Grade 1-2
    127
    41
        Hypomagnesemia: Grade 3
    1
    0
        Hypomagnesemia: Grade 4
    2
    0
        Hyponatremia: Grade 1-2
    107
    44
        Hyponatremia: Grade 3
    11
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of randomization up to 28 days after last dose of study medication (final analysis till study completion, approximately up to 10.8 years)
    Adverse event reporting additional description
    Same event may appear as non-SAE and SAE but are distinct events. Event may be an SAE in 1 participant and non-SAE in other, or participant may have both non-SAE and SAE. AT population included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Placebo Plus Letrozole
    Reporting group description
    		 Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group title
    Palbociclib Plus Letrozole
    Reporting group description
    		 Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Serious adverse events
    		 Placebo Plus Letrozole Palbociclib Plus Letrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 222 (17.12%)
    125 / 444 (28.15%)
         number of deaths (all causes)
    6
    16
         number of deaths resulting from adverse events
    5
    16
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast cancer metastatic
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric cancer
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 222 (0.45%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Disease progression
         subjects affected / exposed
    0 / 222 (0.00%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    General physical health deterioration
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 222 (0.45%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puncture site pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 222 (0.00%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mucosal inflammation
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast haematoma
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 222 (0.45%)
    5 / 444 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 222 (1.35%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Tracheomalacia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organic brain syndrome
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract traumatic
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bell's palsy
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 222 (0.00%)
    8 / 444 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 222 (0.00%)
    5 / 444 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 222 (0.45%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blindness
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lens dislocation
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry age-related macular degeneration
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 222 (0.90%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 222 (0.00%)
    5 / 444 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stag horn calculus
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 222 (0.90%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 222 (2.25%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 222 (0.00%)
    6 / 444 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    COVID-19
         subjects affected / exposed
    2 / 222 (0.90%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Endocarditis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Plus Letrozole Palbociclib Plus Letrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    209 / 222 (94.14%)
    435 / 444 (97.97%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    69 / 222 (31.08%)
    101 / 444 (22.75%)
         occurrences all number
    73
    132
    Hypertension
         subjects affected / exposed
    24 / 222 (10.81%)
    45 / 444 (10.14%)
         occurrences all number
    34
    142
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    20 / 222 (9.01%)
    63 / 444 (14.19%)
         occurrences all number
    25
    106
    Pain
         subjects affected / exposed
    20 / 222 (9.01%)
    44 / 444 (9.91%)
         occurrences all number
    22
    54
    Oedema peripheral
         subjects affected / exposed
    19 / 222 (8.56%)
    65 / 444 (14.64%)
         occurrences all number
    20
    83
    Mucosal inflammation
         subjects affected / exposed
    9 / 222 (4.05%)
    49 / 444 (11.04%)
         occurrences all number
    11
    101
    Fatigue
         subjects affected / exposed
    65 / 222 (29.28%)
    183 / 444 (41.22%)
         occurrences all number
    107
    356
    Asthenia
         subjects affected / exposed
    27 / 222 (12.16%)
    86 / 444 (19.37%)
         occurrences all number
    44
    169
    Influenza like illness
         subjects affected / exposed
    11 / 222 (4.95%)
    36 / 444 (8.11%)
         occurrences all number
    13
    76
    Chest pain
         subjects affected / exposed
    7 / 222 (3.15%)
    31 / 444 (6.98%)
         occurrences all number
    11
    41
    Chills
         subjects affected / exposed
    7 / 222 (3.15%)
    24 / 444 (5.41%)
         occurrences all number
    9
    35
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    10 / 222 (4.50%)
    24 / 444 (5.41%)
         occurrences all number
    11
    26
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    48 / 222 (21.62%)
    127 / 444 (28.60%)
         occurrences all number
    63
    231
    Dyspnoea
         subjects affected / exposed
    35 / 222 (15.77%)
    80 / 444 (18.02%)
         occurrences all number
    43
    109
    Epistaxis
         subjects affected / exposed
    16 / 222 (7.21%)
    43 / 444 (9.68%)
         occurrences all number
    29
    59
    Oropharyngeal pain
         subjects affected / exposed
    9 / 222 (4.05%)
    50 / 444 (11.26%)
         occurrences all number
    11
    74
    Nasal congestion
         subjects affected / exposed
    8 / 222 (3.60%)
    23 / 444 (5.18%)
         occurrences all number
    8
    27
    Rhinorrhoea
         subjects affected / exposed
    4 / 222 (1.80%)
    23 / 444 (5.18%)
         occurrences all number
    4
    27
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    27 / 222 (12.16%)
    45 / 444 (10.14%)
         occurrences all number
    32
    53
    Depression
         subjects affected / exposed
    21 / 222 (9.46%)
    39 / 444 (8.78%)
         occurrences all number
    25
    46
    Insomnia
         subjects affected / exposed
    30 / 222 (13.51%)
    73 / 444 (16.44%)
         occurrences all number
    44
    89
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 222 (5.86%)
    65 / 444 (14.64%)
         occurrences all number
    16
    174
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 222 (6.31%)
    64 / 444 (14.41%)
         occurrences all number
    22
    189
    Neutrophil count decreased
         subjects affected / exposed
    7 / 222 (3.15%)
    106 / 444 (23.87%)
         occurrences all number
    9
    1166
    Platelet count decreased
         subjects affected / exposed
    1 / 222 (0.45%)
    38 / 444 (8.56%)
         occurrences all number
    2
    203
    Weight decreased
         subjects affected / exposed
    10 / 222 (4.50%)
    30 / 444 (6.76%)
         occurrences all number
    18
    53
    White blood cell count decreased
         subjects affected / exposed
    4 / 222 (1.80%)
    83 / 444 (18.69%)
         occurrences all number
    7
    625
    Blood creatinine increased
         subjects affected / exposed
    8 / 222 (3.60%)
    33 / 444 (7.43%)
         occurrences all number
    11
    109
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    18 / 222 (8.11%)
    60 / 444 (13.51%)
         occurrences all number
    21
    86
    Contusion
         subjects affected / exposed
    6 / 222 (2.70%)
    24 / 444 (5.41%)
         occurrences all number
    6
    28
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    34 / 222 (15.32%)
    80 / 444 (18.02%)
         occurrences all number
    43
    122
    Dysgeusia
         subjects affected / exposed
    7 / 222 (3.15%)
    37 / 444 (8.33%)
         occurrences all number
    9
    48
    Headache
         subjects affected / exposed
    62 / 222 (27.93%)
    109 / 444 (24.55%)
         occurrences all number
    103
    197
    Paraesthesia
         subjects affected / exposed
    9 / 222 (4.05%)
    26 / 444 (5.86%)
         occurrences all number
    10
    36
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 222 (10.36%)
    125 / 444 (28.15%)
         occurrences all number
    62
    471
    Thrombocytopenia
         subjects affected / exposed
    4 / 222 (1.80%)
    64 / 444 (14.41%)
         occurrences all number
    5
    211
    Neutropenia
         subjects affected / exposed
    8 / 222 (3.60%)
    308 / 444 (69.37%)
         occurrences all number
    16
    3898
    Leukopenia
         subjects affected / exposed
    2 / 222 (0.90%)
    115 / 444 (25.90%)
         occurrences all number
    2
    798
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    2 / 222 (0.90%)
    33 / 444 (7.43%)
         occurrences all number
    5
    46
    Cataract
         subjects affected / exposed
    7 / 222 (3.15%)
    28 / 444 (6.31%)
         occurrences all number
    8
    37
    Dry eye
         subjects affected / exposed
    10 / 222 (4.50%)
    28 / 444 (6.31%)
         occurrences all number
    10
    32
    Vision blurred
         subjects affected / exposed
    7 / 222 (3.15%)
    23 / 444 (5.18%)
         occurrences all number
    7
    27
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    12 / 222 (5.41%)
    28 / 444 (6.31%)
         occurrences all number
    19
    38
    Diarrhoea
         subjects affected / exposed
    51 / 222 (22.97%)
    136 / 444 (30.63%)
         occurrences all number
    95
    372
    Constipation
         subjects affected / exposed
    36 / 222 (16.22%)
    105 / 444 (23.65%)
         occurrences all number
    46
    149
    Abdominal pain upper
         subjects affected / exposed
    20 / 222 (9.01%)
    41 / 444 (9.23%)
         occurrences all number
    31
    57
    Abdominal distension
         subjects affected / exposed
    14 / 222 (6.31%)
    21 / 444 (4.73%)
         occurrences all number
    16
    32
    Dyspepsia
         subjects affected / exposed
    29 / 222 (13.06%)
    52 / 444 (11.71%)
         occurrences all number
    36
    65
    Abdominal pain
         subjects affected / exposed
    15 / 222 (6.76%)
    67 / 444 (15.09%)
         occurrences all number
    23
    96
    Vomiting
         subjects affected / exposed
    37 / 222 (16.67%)
    80 / 444 (18.02%)
         occurrences all number
    75
    159
    Stomatitis
         subjects affected / exposed
    15 / 222 (6.76%)
    76 / 444 (17.12%)
         occurrences all number
    21
    166
    Nausea
         subjects affected / exposed
    59 / 222 (26.58%)
    169 / 444 (38.06%)
         occurrences all number
    119
    305
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 222 (3.60%)
    37 / 444 (8.33%)
         occurrences all number
    11
    47
    Toothache
         subjects affected / exposed
    7 / 222 (3.15%)
    23 / 444 (5.18%)
         occurrences all number
    8
    29
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    36 / 222 (16.22%)
    150 / 444 (33.78%)
         occurrences all number
    37
    164
    Dry skin
         subjects affected / exposed
    16 / 222 (7.21%)
    66 / 444 (14.86%)
         occurrences all number
    16
    99
    Pruritus
         subjects affected / exposed
    11 / 222 (4.95%)
    49 / 444 (11.04%)
         occurrences all number
    18
    98
    Rash
         subjects affected / exposed
    24 / 222 (10.81%)
    79 / 444 (17.79%)
         occurrences all number
    32
    137
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    89 / 222 (40.09%)
    187 / 444 (42.12%)
         occurrences all number
    161
    359
    Back pain
         subjects affected / exposed
    52 / 222 (23.42%)
    117 / 444 (26.35%)
         occurrences all number
    85
    192
    Bone pain
         subjects affected / exposed
    24 / 222 (10.81%)
    45 / 444 (10.14%)
         occurrences all number
    33
    75
    Muscle spasms
         subjects affected / exposed
    13 / 222 (5.86%)
    46 / 444 (10.36%)
         occurrences all number
    20
    63
    Musculoskeletal chest pain
         subjects affected / exposed
    11 / 222 (4.95%)
    37 / 444 (8.33%)
         occurrences all number
    15
    57
    Myalgia
         subjects affected / exposed
    20 / 222 (9.01%)
    65 / 444 (14.64%)
         occurrences all number
    34
    90
    Neck pain
         subjects affected / exposed
    12 / 222 (5.41%)
    27 / 444 (6.08%)
         occurrences all number
    16
    39
    Pain in extremity
         subjects affected / exposed
    41 / 222 (18.47%)
    99 / 444 (22.30%)
         occurrences all number
    65
    158
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    3 / 222 (1.35%)
    31 / 444 (6.98%)
         occurrences all number
    8
    69
    Sinusitis
         subjects affected / exposed
    9 / 222 (4.05%)
    30 / 444 (6.76%)
         occurrences all number
    19
    61
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 222 (11.71%)
    75 / 444 (16.89%)
         occurrences all number
    40
    136
    Urinary tract infection
         subjects affected / exposed
    20 / 222 (9.01%)
    71 / 444 (15.99%)
         occurrences all number
    43
    154
    Nasopharyngitis
         subjects affected / exposed
    25 / 222 (11.26%)
    95 / 444 (21.40%)
         occurrences all number
    39
    174
    Influenza
         subjects affected / exposed
    6 / 222 (2.70%)
    24 / 444 (5.41%)
         occurrences all number
    7
    29
    Rhinitis
         subjects affected / exposed
    0 / 222 (0.00%)
    24 / 444 (5.41%)
         occurrences all number
    0
    27
    Bronchitis
         subjects affected / exposed
    7 / 222 (3.15%)
    27 / 444 (6.08%)
         occurrences all number
    11
    35
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 222 (9.46%)
    86 / 444 (19.37%)
         occurrences all number
    24
    125
    Hypokalaemia
         subjects affected / exposed
    8 / 222 (3.60%)
    28 / 444 (6.31%)
         occurrences all number
    9
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2013
    Amendment 1: For France only: Clarification of inclusion criterion #10
    03 Jan 2014
    Amendment 2: Clarification of inclusion criterion #10 and 4; Clarification of exclusion criterion #1 and 17; Added preliminary results; Added recommendation to take palbociclib with a meal; Added prohibition to take proton-pump inhibitors; Added recommendation to use local antacids as well as H2-receptor antagonist; Editorial changes were done to address typo and align protocol language with clarified criteria.
    21 Mar 2014
    Amendment 3: Added ophthalmic procedures; Included preliminary results from a preclinical ocular study with palbociclib in rats; Clarified that safety related assessments must continue if participants continue study treatment beyond RECIST defined disease progression; Changes done to align with updated protocol template; Electrocardiogram: Definition of “evaluable” participant revised; Ocular Safety Assessment and Adverse Event Reporting: were added; sample size was revised; Section 15.1 and Appendix 6 FACT-B: updated; Appendix 8 was added.
    18 Sep 2014
    Amendment 4: Added prospective monitoring of hemoglobin A1c; Ocular Preclinical Date: Updated section to report emergent data findings from the 27-week rat toxicity study; updated study design to reflect Sponsor’s decision to no longer require safety review by an internal oncology business unit safety data monitoring committee (IOBU-SDMC) for studies already monitored by an external data monitoring committee (E-DMC). Language related to cycle delay further defined to clearly state that any new cycle may only start if blinded study treatment can be resumed. Provided results from study A5481038 designed to investigate the effect of H2-receptor antagonists, proton pump inhibitors and local antacids; Editorial changes to differentiate between strong and moderate CYP3A inducers/inhibitors and to reflect current Sponsor protocol template.
    02 Dec 2014
    Amendment 5: Changed the interim analysis efficacy boundary from O’Brien-Fleming to Haybittle-Peto boundary to ensure that the study would only be stopped at the interim analysis if the primary analysis (PFS) results are statistically significant, and clinically meaningful and editorial changes to reflect current instructions for investigational product destruction at the end of the trial. Prohibited Medications: Strong/Moderate CYP3A inducers/inhibitors and proton-pump inhibitors are allowed for participants who permanently discontinue blinded therapy and continue on study with letrozole monotherapy only. Analysis of Primary Endpoint: Editorial change to clarify planned analyses.
    07 Apr 2015
    Amendment 6: Analysis Secondary Endpoints: Changes reflecting the collection of Patient Reported Outcome data during the post-progression follow-up period to assess potential impact of post-progression status on participants quality of life and editorial changes to reflect current Sponsor’s protocol template.
    15 Oct 2015
    Amendment 7: Protocol language revised to reflect that collection of disease progression dates on subsequent anticancer therapy to better understand the potential influence of palbociclib response to subsequent anticancer therapies. Additional language was also added to clarify that the 7-day off treatment period in any given cycle should always be respected.
    21 May 2018
    Amendment 8: Added summary of the results from the primary analysis to support changes made in the body of the protocol. Clarified that the third-party core imaging laboratory will no longer perform blinded independent central review of tumor imaging scans and thus, the investigators will no longer be required to send the scans to the independent core imaging laboratory. Clarified that upon IRB/IEC approval of Amendment 8, new cycle Day 1 procedures (ie, physical examination, ECOG performance status, ECG, Quality of Life questionnaires, blood chemistry, hematology) that were performed prior to knowing the need to delay the start of the cycle do not need to be repeated unless required to determine whether study drug may be resumed. Chest CT scans will no longer be a required safety assessment to reflect that the choice of modality for tumor assessment is left at the investigator’s discretion upon approval of Amendment 8.

    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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