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    Clinical Trial Results:
    MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 3 TRIAL OF FULVESTRANT (FASLODEX) WITH OR WITHOUT PD-0332991 (PALBOCICLIB) ±GOSERELIN IN WOMEN WITH HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE THERAPY

    Summary
    EudraCT number
    		 2013-002580-26
    Trial protocol
    		 BE   NL   IE   IT   GB   DE   PT   FR  
    Global end of trial date
    28 Sep 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Sep 2023
    First version publication date
    17 Mar 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    A5481023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01942135
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 East 42nd Street,, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 800 718 1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 800 718 1021, 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
    28 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of palbociclib in combination with fulvestrant (with or without goserelin) over fulvestrant (with or without goserelin) along with prolonging investigator-assessed PFS in women with HR-positive/ HER2-negative metastatic breast cancer whose disease had progressed on prior endocrine therapy.
    Protection of trial subjects
    The study was conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Conference on Harmonisation [ICH] 1996), and the Declaration of Helsinki (World Medical Association 1996 and 2008). In addition, the study was conducted in accordance with the protocol, the ICH guideline on GCP, and applicable local regulatory requirements and laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Korea, Republic of: 43
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 44
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 201
    Worldwide total number of subjects
    521
    EEA total number of subjects
    92
    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)
    392
    From 65 to 84 years
    126
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 144 sites in 17 countries that randomized 521 subjects. Eligible subjects were to have histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of recurrent (local or metastatic) disease.

    Pre-assignment
    Screening details
    		 The study consisted of a screening within 28 days before randomization, an active treatment phase, divided in cycles of 28 days each, and a posttreatment follow-up period during which survival and new anti-cancer therapy information was collected every 3 months for the first 9 months, then every 6 months from the last dose of study intervention.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The blinding details was either a manual or electronic process. Blinding codes were only broken in emergency for reasons of participants safety, or if the participant discontinued treatment due to disease progression, as determined by the study physician using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 criteria.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Palbociclib + Fulvestrant
    Arm description
    		 Subjects were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    PD-0332991
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose of 125 mg per day continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days.

    Arm title
    		 Placebo + Fulvestrant
    Arm description
    		 Subjects were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo orally dosed for 3 weeks continuously followed by 1 week off; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days.

    Number of subjects in period 1
    		Palbociclib + Fulvestrant Placebo + Fulvestrant
    Started
    347
    174
    Treated
    345
    172
    Completed
    0
    0
    Not completed
    347
    174
         Consent withdrawn by subject
    4
    3
         Global deterioration of health status
    9
    6
         Adverse Event
    21
    7
         Randomized not treated
    2
    2
         Death
    2
    1
         Not specified
    19
    4
         Objective progression + progressive disease
    279
    148
         Protocol deviation
    1
    -
         Subject refused to continue treatment
    10
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palbociclib + Fulvestrant
    Reporting group description
    		 Subjects were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 Subjects were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.

    Reporting group values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant Total
    Number of subjects
    		 347 174 521
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 261 131 392
        From 65-84 years
    		 83 43 126
        85 years and over
    		 3 0 3
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 56.9 ( 11.7 ) 56.8 ( 10.4 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 347 174 521
        Male
    		 0 0 0
    Menopausal Status
    Units: Subjects
        Postmenopausal
    		 275 138 413
        Pre/perimenopausal
    		 72 36 108
    Race
    Units: Subjects
        White
    		 252 133 385
        Black
    		 12 8 20
        Asian
    		 74 31 105
        Other
    		 8 1 9
        Unspecified
    		 1 1 2
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 17 11 28
        Not Hispanic/Latino
    		 329 161 490
        Unspecified
    		 1 2 3
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 161.1 ( 7.0 ) 161.3 ( 7.6 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 70.4 ( 17.5 ) 72.0 ( 17.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Palbociclib + Fulvestrant
    Reporting group description
    		 Subjects were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.

    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 Subjects were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.

    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 which was defined as the time from the date of randomization to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD. PFS data were censored on the date of the last tumor assessment on study for subjects who did not have objective tumor progression and who did not die while on study. Subjects lacking an evaluation of tumor response after randomization had their PFS time censored on the date of randomization with the duration of one day. Subjects with documentation of PD or death after a long interval (ie, 2 or more incomplete or non-evaluable assessments) since the last tumor assessment were censored at the time of last objective assessment that did not show PD. The length of PFS was calculated as PFS time (months) = [progression/death date (censor date) - randomization date + 1]/30.4.
    End point type
    Primary
    End point timeframe
    From randomization date to date of first documentation of progression or death (assessed up to 2 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: months
        median (confidence interval 95%)
    11.2 (9.5 to 12.9)
    4.6 (3.5 to 5.6)
    Statistical analysis title
    		 Statistical analysis for PFS
    Statistical analysis description
    The primary hypothesis to be tested was H0: λ≥1 versus. HA: λ<1, where λ was the palbociclib plus fulvestrant: placebo plus fulvestrant hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Fulvestrant. The study was planned to have 90% power and control the type-I error rate at 0.025.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Stratified Log Rank Test (1-sided)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.497
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.398
         upper limit
    		 0.62

    Secondary: Overall Survival (OS) - Number of Subjects Who Died

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    End point title
    		 Overall Survival (OS) - Number of Subjects Who Died
    End point description
    OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the subject was known to be alive. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Subjects lacking survival data beyond randomization were to have their OS times be censored at randomization. The length of OS was calculated as OS time (months) = [death date (censor date) – randomization date + 1]/30.4.
    End point type
    Secondary
    End point timeframe
    From randomization until death (up to 4.5 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: Subjects
    201
    109
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the subject was known to be alive. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Subjects lacking survival data beyond randomization were to have their OS times be censored at randomization. The length of OS was calculated as OS time (months) = [death date (censor date) – randomization date + 1]/30.4.
    End point type
    Secondary
    End point timeframe
    From randomization until death (up to 4.5 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: months
        median (confidence interval 95%)
    34.9 (28.8 to 40.0)
    28.0 (23.6 to 34.6)
    Statistical analysis title
    		 Statistical analysis for OS
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0429 [1]
    Method
    		 Stratified Log Rank Test (1-sided)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.814
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.644
         upper limit
    		 1.029
    Notes
    [1] - 1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior endocrine therapy per randomization.

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

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    End point title
    		 Survival Probabilities at Year 1, Year 2, and Year 3
    End point description
    One-, Two- or Three-year Survival Probability is defined as the probability of survival 1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate. Survival time was censored to last date the subject is known to be alive.
    End point type
    Secondary
    End point timeframe
    From randomization until death (assessed up to 36 months)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: Survival Probability
    number (confidence interval 95%)
        Survival Probability at Year 1
    85.5 (81.3 to 88.9)
    84.8 (78.3 to 89.4)
        Survival Probability at Year2
    65.3 (59.9 to 70.2)
    57.3 (49.2 to 64.6)
        Survival Probability at Year 3
    49.6 (44.0 to 54.9)
    40.8 (32.9 to 48.5)
    No statistical analyses for this end point

    Secondary: Objective Response (OR)

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    End point title
    		 Objective Response (OR)
    End point description
    OR is defined as the overall complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) Objective Response Rate (ORR) is defined as the proportion of participants with CR or PR relative to (1) all randomized participants and (2) randomized participants with measurable disease at baseline. Designation of best response of stable disease (SD) requires the criteria to be met at least 8 weeks after randomization. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Percentage of participants with confirmed objective tumor response is mentioned below.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (assessed up to 2 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: percentage of participants
        number (confidence interval 95%)
    21.0 (16.9 to 25.7)
    8.6 (4.9 to 13.8)
    Statistical analysis title
    		 Statistical analysis for OR
    Statistical analysis description
    The exact test is testing the null hypothesis that the odds ratio of objective response rate is less than or equal to 1 vs. the alternative hypothesis that the odds ratio of objective response rate is greater than 1. An Odds Ratio >1 means better response in favor of palbociclib plus fulvestrant arm.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [2]
    Method
    		 Exact test (1-sided)
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.783
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.563
         upper limit
    		 5.603
    Notes
    [2] - The p-value was not adjusted for multiple comparisons. The priori threshold for statistical significance is 1-sided, alpha=0.025.

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as [the date response ended (ie, date of PD or death) – first CR or PR date + 1)]/30.4. DR was only be calculated for the subgroup of participants with an objective tumor response. Kaplan-Meier estimate of median of the DR is provided below. No inferential statistical analysis were done for DR.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (assessed up to 2 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: Months
        median (confidence interval 95%)
    10.4 (8.3 to 999999)
    9.0 (5.6 to 999999)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Response (CBR)

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    End point title
    		 Clinical Benefit Response (CBR)
    End point description
    CBR is defined as the overall complete response (CR), partial response (PR) , or stable disease (SD) ≥24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Clinical Benefit Response Rate (CBRR) is defined as the proportion of participants with CR, PR, or SD ≥24 weeks relative to (1) all randomized participants and (2) randomized participants with measurable disease at baseline. Designation of best response of SD ≥24 weeks requires the criteria to be met at least 24 weeks after randomization. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, a best response of SD ≥24 weeks, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR and a best response of SD ≥24 weeks was counted as non-responders in the assessment of CBR.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (assessed up to 2 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: percentage of participants
        number (confidence interval 95%)
    66.3 (61.0 to 71.2)
    39.7 (32.3 to 47.3)
    Statistical analysis title
    		 Statistical analysis of CBR
    Statistical analysis description
    The exact test is testing the null hypothesis that the odds ratio of objective response rate is less than or equal to 1 vs. the alternative hypothesis that the odds ratio of objective response rate is greater than 1. An Odds Ratio >1 means better response in favor of palbociclib plus fulvestrant arm.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Exact test (1-sided)
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.046
         upper limit
    		 4.565
    Notes
    [3] - The p-value was not adjusted for multiple comparisons. The priori threshold for statistical significance is 1-sided, alpha=0.025.

    Secondary: Observed Plasma Trough Concentration (Ctrough) for Palbociclib

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    End point title
    		 Observed Plasma Trough Concentration (Ctrough) for Palbociclib [4]
    End point description
    Ctrough was defined as steady-state predose concentration. Observed directly from data. For palbociclib, a steady-state trough was to be defined as a predose plasma concentration following at least 8 consecutive days of 125 mg daily dose without dosing interruption and the time window for the PK collection was to be between 22 and 26 hours after the dose (the day prior to PK collection) and no more than 1 hour post-dose on the day of PK collection. The subjects who were treated with Palbociclib + fulvestrant (with or without goserelin) or placebo + fulvestrant (with or without goserelin) and have at least one measured plasma drug concentration. The geometric mean and coefficient of variation was not estimable for Cycle 1/Day 15 and Cycle 2/Day 15 for the reporting arm placebo plus fulvestrant.
    End point type
    Secondary
    End point timeframe
    Cycle 1/Day 15 and Cycle 2/Day 15
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The 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.
    End point values
    		 Palbociclib + Fulvestrant
    Number of subjects analysed
    347
    Units: nanograms per millilitre (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1/Day 15 (N= 165)
    70.70 ( 44 )
        Cycle 2/Day 15 (N= 160)
    75.29 ( 44 )
    No statistical analyses for this end point

    Secondary: Ctrough for Fulvestrant

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    End point title
    		 Ctrough for Fulvestrant
    End point description
    Ctrough was defined as steady-state predose concentration. Observed directly from data. For fulvestrant, a steady-state trough was to be defined when a patient had received all prior planned doses and the sample was collected predose. The 40 subjects who participated in the early safety review, who are treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ± goserelin and have at least one measured plasma drug concentration.
    End point type
    Secondary
    End point timeframe
    Cycles 2/Day 1 and Cycle 3/Day 1
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 2/Day 1 (N= 35, 19)
    11.75 ( 41 )
    9.31 ( 52 )
        Cycle 3/Day 1 (N= 29, 14)
    9.90 ( 42 )
    7.60 ( 72 )
    No statistical analyses for this end point

    Secondary: Ctrough for Goserelin

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    End point title
    		 Ctrough for Goserelin
    End point description
    Ctrough was defined as steady-state predose concentration. Observed directly from data. For goserelin, a steady-state trough was to be defined when a patient had received all prior planned doses and the sample was collected predose. The 40 subjects who participated in the early safety review, who are treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ± goserelin and have at least one measured plasma drug concentration.
    End point type
    Secondary
    End point timeframe
    Cycles 2/ Day 1 and Cycle 3/ Day 1
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    347
    174
    Units: picograms per millilitre (pg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 2/Day 1 (N= 9, 5)
    295.1 ( 153 )
    302.5 ( 74 )
        Cycle 3/Day 1 (N= 7, 3)
    344.8 ( 64 )
    288.5 ( 40 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores
    End point description
    The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from “not at all” to “very much” and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Global health status / QoL
    -0.9 (-2.5 to 0.7)
    -4.0 (-6.3 to -1.7)
        Physical functioning
    -0.7 (-2.1 to 0.7)
    -1.7 (-3.7 to 0.2)
        Role functioning
    -1.8 (-3.7 to 0.1)
    -3.7 (-6.5 to -0.9)
        Emotional functioning
    2.7 (1.1 to 4.3)
    -1.9 (-4.2 to 0.5)
        Cognitive functioning
    -1.7 (-3.1 to -0.2)
    -2.9 (-5.0 to -0.7)
        Social functioning
    -0.5 (-2.5 to 1.5)
    -0.6 (-3.4 to 2.3)
    Statistical analysis title
    		 Statistical significance for Global health status
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0313 [5]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 6
    Notes
    [5] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for physical functioning
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4 [6]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 3.5
    Notes
    [6] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for role functioning
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2615 [7]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 5.3
    Notes
    [7] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for emotional functioning
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016 [8]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 7.4
    Notes
    [8] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for cognitive functioning
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.365 [9]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 3.8
    Notes
    [9] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for social functioning
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9615 [10]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 3.5
    Notes
    [10] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.

    Secondary: Change from Baseline in EORTC QLQ-C30 Symptom Scale Scores

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    End point title
    		 Change from Baseline in EORTC QLQ-C30 Symptom Scale Scores
    End point description
    The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from “not at all” to “very much” and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Fatigue
    1.8 (0.1 to 3.5)
    3.3 (0.9 to 5.8)
        Nausea and vomiting
    1.7 (0.4 to 3.0)
    4.2 (2.3 to 6.1)
        Pain
    -3.3 (-5.1 to -1.5)
    2.0 (-0.6 to 4.6)
        Dyspnoea
    2.8 (1.0 to 4.7)
    3.3 (0.6 to 6.0)
        Insomnia
    -2.4 (-4.4 to -0.4)
    -0.4 (-3.3 to 2.5)
        Appetite loss
    1.1 (-0.8 to 3.1)
    1.7 (-1.1 to 4.6)
        Constipation
    3.5 (1.7 to 5.3)
    2.8 (0.1 to 5.4)
        Diarrhoea
    1.9 (0.6 to 3.1)
    2.4 (0.5 to 4.3)
        Financial difficulties
    -3.7 (-5.6 to -1.9)
    -4.0 (-6.7 to -1.3)
    Statistical analysis title
    		 Statistical significance for fatigue
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32 [11]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 1.5
    Notes
    [11] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for nausea/vomiting
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0369 [12]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 -0.2
    Notes
    [12] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for pain
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0011 [13]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 -2.1
    Notes
    [13] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for dyspnoea
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7699 [14]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 2.8
    Notes
    [14] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for insomnia
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2721 [15]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 1.6
    Notes
    [15] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for appetite loss
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7334 [16]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 2.9
    Notes
    [16] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for constipation
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6491 [17]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 3.9
    Notes
    [17] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for diarrhoea
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6293 [18]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 1.7
    Notes
    [18] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for financial difficulty
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8812 [19]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 3.6
    Notes
    [19] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores
    End point description
    The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from ’not at all’ to ’very much’. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Body image
    1.9 (0.2 to 3.6)
    -0.3 (-2.8 to 2.1)
        Sexual functioning
    -1.1 (-2.5 to 0.2)
    -0.4 (-2.3 to 1.5)
        Sexual enjoyment
    -5.2 (-8.3 to -2.1)
    -6.6 (-11.6 to -1.7)
        Future perspective
    8.1 (5.8 to 10.4)
    4.5 (1.2 to 7.9)
    Statistical analysis title
    		 Statistical significance for body image
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1386 [20]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 5.2
    Notes
    [20] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for future perspective
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0845 [21]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 7.6
    Notes
    [21] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for sexual enjoyment
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6271 [22]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 7.3
    Notes
    [22] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for sexual functioning
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5235 [23]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 1.6
    Notes
    [23] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.

    Secondary: Change from Baseline in EORTC QLQ BR23 Symptom Scale Scores

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    End point title
    		 Change from Baseline in EORTC QLQ BR23 Symptom Scale Scores
    End point description
    The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from ’not at all’ to ’very much’. All scores are converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represent more severe symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Systemic therapy side effects
    3.8 (2.6 to 4.9)
    3.4 (1.8 to 5.0)
        Breast symptoms
    -2.2 (-3.2 to -1.3)
    -1.3 (-2.7 to 0.0)
        Arm symptoms
    -2.2 (-3.6 to -0.9)
    -2.0 (-4.0 to -0.1)
        Upset by hair loss
    2.9 (-1.7 to 7.4)
    -6.0 (-12.3 to 0.3)
    Statistical analysis title
    		 Statistical significance for systemic therapy
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7273 [24]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 2.3
    Notes
    [24] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for arm symptoms
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.875 [25]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 2.2
    Notes
    [25] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for upset by hair loss
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0255 [26]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 16.6
    Notes
    [26] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
    Statistical analysis title
    		 Statistical significance for breast symptoms
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2671 [27]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 0.7
    Notes
    [27] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.

    Secondary: Change from Baseline in EuroQoL 5D (EQ-5D)- Health Index scores

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    End point title
    		 Change from Baseline in EuroQoL 5D (EQ-5D)- Health Index scores
    End point description
    The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a three level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/ impairment Published weights are available that allow for the creation of a single summary score called the EQ-5D index, which basically ranges from 0 to 1 with low scores representing a higher level of dysfunction and 1 as perfect health. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    0.006 (-0.01 to 0.03)
    -0.031 (-0.06 to 0.00)
    Statistical analysis title
    		 Statistical Analysis for EQ-5D-Health Index scores
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0308 [28]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.07
    Notes
    [28] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.

    Secondary: Change from Baseline in EQ-5D Visual Analog Scale (VAS) scores scale

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    End point title
    		 Change from Baseline in EQ-5D Visual Analog Scale (VAS) scores scale
    End point description
    The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    -1.8 (-3.3 to -0.3)
    -2.6 (-4.8 to -0.4)
    Statistical analysis title
    		 Statistical Analysis for EQ-5D VAS scores scale
    Statistical analysis description
    Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5523 [29]
    Method
    		 Mixed Model Analysis (2-sided)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 3.5
    Notes
    [29] - The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.

    Secondary: Time to Deterioration (TTD)

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    End point title
    		 Time to Deterioration (TTD)
    End point description
    A time to event analysis was pre-specified for pain. An analysis of TTD in pain defined as time between baseline and first occurrence of increase of ≥10 points in pain. Deterioration will be defined increase in score of 10 points or greater from baseline. The Kaplan-Meier estimates of quartiles (time to deterioration) with 95% CI is mentioned below.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    335
    166
    Units: Units on a scale
    median (confidence interval 95%)
        25% quartile
    1.9 (1.2 to 2.2)
    1.0 (1.0 to 1.9)
        50% quartile
    8.0 (5.6 to 999999)
    2.8 (2.3 to 5.4)
    Statistical analysis title
    		 Statistical Analysis 1 for TTD
    Statistical analysis description
    Treatment with palbociclib plus fulvestrant significantly delayed TTD in pain symptom compared with placebo plus fulvestrant for unstratified analysis.
    Comparison groups
    Palbociclib + Fulvestrant v Placebo + Fulvestrant
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [30]
    Method
    		 Unstratified log-rank test (1-sided)
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.642
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.487
         upper limit
    		 0.846
    Notes
    [30] - The priori threshold for statistical significance is 1-sided alpha=0.025. The p-value was not adjusted for multiple comparisons.

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

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs; All Causalities)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death; is life-threatening; requires hospitalization; results in persistent or significant disability or in congenital anomaly/birth defect. Severity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.
    End point type
    Secondary
    End point timeframe
    From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years).
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    345
    172
    Units: percentage of subjects
    number (not applicable)
        With AEs
    98.8
    93.6
        With SAEs
    22.6
    19.2
        With Grade 3 or 4 AEs
    80.6
    26.7
        With Grade 5 AEs
    2.3
    1.7
        Discontinued palbociclib/placebo due to AEs
    7.5
    4.7
    No statistical analyses for this end point

    Secondary: Subjects With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Laboratory Results

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    End point title
    		 Subjects With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Laboratory Results
    End point description
    Number of subjects with shifts from Grade ≤2 at baseline values to post-baseline values (shift to Grade 3 or 4) were reported as per NCI-CTCAE, V4.0 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Shifts in lab parameter from Grade ≤2 at baseline to Grade 3 or 4 postbaseline (for parameters Anemia, Hemoglobin increased, Neutrophil count decreased, Platelet count decreased, and White blood cell count decreased) were reported.
    End point type
    Secondary
    End point timeframe
    From baseline to end of treatment/withdrawal (up to 4.5 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    343
    172
    Units: Subjects
        Anemia
    16
    3
        Hemoglobin increased
    1
    0
        Neutrophil count decreased
    239
    1
        Platelet count decreased
    10
    0
        White blood cell count decreased
    167
    0
    No statistical analyses for this end point

    Secondary: Subjetcs With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Laboratory Results

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    End point title
    		 Subjetcs With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Laboratory Results
    End point description
    Number of subjects with shifts from Grade ≤2 at baseline values to post-baseline values (shift to Grade 3 or 4) were reported as per NCI-CTCAE, V4.0 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Shifts in lab parameter from Grade ≤2 at baseline to Grade 3 or 4 postbaseline (for parameters ALT increased, ALP increased, AST increased, Blood bilirubin increased, Creatinine increased, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hypoalbuminemia, Hypocalcemia, Hypokalemia, Hypomagnesemia, and Hyponatremia) were reported.
    End point type
    Secondary
    End point timeframe
    From baseline to end of treatment/withdrawal (up to 4.5 years)
    End point values
    		 Palbociclib + Fulvestrant Placebo + Fulvestrant
    Number of subjects analysed
    343
    172
    Units: Subjects
        ALT increased
    10
    1
        ALP increased
    2
    2
        AST increased
    13
    7
        Blood bilirubin increased
    2
    3
        Creatinine increased
    5
    0
        Hypercalcemia
    1
    0
        Hyperkalemia
    2
    2
        Hypermagnesemia
    7
    2
        Hypernatremia
    0
    1
        Hypoalbuminemia
    0
    1
        Hypocalcemia
    2
    2
        Hypokalemia
    0
    0
        Hypomagnesemia
    0
    0
        Hyponatremia
    12
    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 calendar days (±7 days) after last dose of study intervention (up to 8.4 years).
    Adverse event reporting additional description
    The safety analysis set included all subjects who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo + Fulvestrant
    Reporting group description
    		 Subjects were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.

    Reporting group title
    Palbociclib + Fulvestrant
    Reporting group description
    		 Subjects were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.

    Serious adverse events
    		 Placebo + Fulvestrant Palbociclib + Fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 172 (19.19%)
    78 / 345 (22.61%)
         number of deaths (all causes)
    5
    9
         number of deaths resulting from adverse events
    5
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         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
    0 / 172 (0.00%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 345 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    General physical health deterioration
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 172 (0.58%)
    5 / 345 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         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
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site fibrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 172 (1.74%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 345 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         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
    Humerus fracture
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sedation complication
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heat illness
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal convulsions
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial spasm
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         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
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 345 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukopenia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         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
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    2 / 172 (1.16%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         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
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric volvulus
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn’s disease
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia, obstructive
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholelithiasis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypothyroidism
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 172 (1.16%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 345 (0.58%)
         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
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 172 (1.16%)
    3 / 345 (0.87%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasopharyngitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         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 / 172 (0.00%)
    2 / 345 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 345 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 345 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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 + Fulvestrant Palbociclib + Fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    161 / 172 (93.60%)
    341 / 345 (98.84%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    30 / 172 (17.44%)
    57 / 345 (16.52%)
         occurrences all number
    32
    85
    Hypertension
         subjects affected / exposed
    6 / 172 (3.49%)
    26 / 345 (7.54%)
         occurrences all number
    7
    52
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 172 (8.14%)
    27 / 345 (7.83%)
         occurrences all number
    17
    38
    Chest pain
         subjects affected / exposed
    11 / 172 (6.40%)
    16 / 345 (4.64%)
         occurrences all number
    16
    19
    Fatigue
         subjects affected / exposed
    56 / 172 (32.56%)
    151 / 345 (43.77%)
         occurrences all number
    89
    301
    Injection site pain
         subjects affected / exposed
    19 / 172 (11.05%)
    26 / 345 (7.54%)
         occurrences all number
    25
    40
    Oedema peripheral
         subjects affected / exposed
    13 / 172 (7.56%)
    36 / 345 (10.43%)
         occurrences all number
    13
    44
    Pain
         subjects affected / exposed
    14 / 172 (8.14%)
    20 / 345 (5.80%)
         occurrences all number
    16
    28
    Pyrexia
         subjects affected / exposed
    9 / 172 (5.23%)
    44 / 345 (12.75%)
         occurrences all number
    11
    64
    Influenza like illness
         subjects affected / exposed
    5 / 172 (2.91%)
    34 / 345 (9.86%)
         occurrences all number
    8
    62
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 172 (13.37%)
    79 / 345 (22.90%)
         occurrences all number
    39
    97
    Dyspnoea
         subjects affected / exposed
    15 / 172 (8.72%)
    50 / 345 (14.49%)
         occurrences all number
    17
    67
    Epistaxis
         subjects affected / exposed
    4 / 172 (2.33%)
    25 / 345 (7.25%)
         occurrences all number
    4
    27
    Oropharyngeal pain
         subjects affected / exposed
    14 / 172 (8.14%)
    53 / 345 (15.36%)
         occurrences all number
    18
    63
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 172 (5.81%)
    20 / 345 (5.80%)
         occurrences all number
    13
    25
    Depression
         subjects affected / exposed
    10 / 172 (5.81%)
    27 / 345 (7.83%)
         occurrences all number
    11
    36
    Insomnia
         subjects affected / exposed
    17 / 172 (9.88%)
    46 / 345 (13.33%)
         occurrences all number
    18
    78
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 172 (1.16%)
    84 / 345 (24.35%)
         occurrences all number
    6
    667
    Platelet count decreased
         subjects affected / exposed
    0 / 172 (0.00%)
    43 / 345 (12.46%)
         occurrences all number
    0
    126
    White blood cell count decreased
         subjects affected / exposed
    7 / 172 (4.07%)
    107 / 345 (31.01%)
         occurrences all number
    10
    581
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 172 (7.56%)
    42 / 345 (12.17%)
         occurrences all number
    21
    66
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 172 (5.23%)
    32 / 345 (9.28%)
         occurrences all number
    14
    55
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 172 (6.40%)
    13 / 345 (3.77%)
         occurrences all number
    14
    14
    Blood creatinine increased
         subjects affected / exposed
    3 / 172 (1.74%)
    20 / 345 (5.80%)
         occurrences all number
    4
    36
    Weight decreased
         subjects affected / exposed
    5 / 172 (2.91%)
    18 / 345 (5.22%)
         occurrences all number
    7
    28
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 172 (2.33%)
    20 / 345 (5.80%)
         occurrences all number
    4
    21
    Fall
         subjects affected / exposed
    13 / 172 (7.56%)
    18 / 345 (5.22%)
         occurrences all number
    14
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 172 (10.47%)
    59 / 345 (17.10%)
         occurrences all number
    21
    101
    Dysgeusia
         subjects affected / exposed
    5 / 172 (2.91%)
    18 / 345 (5.22%)
         occurrences all number
    6
    24
    Headache
         subjects affected / exposed
    38 / 172 (22.09%)
    102 / 345 (29.57%)
         occurrences all number
    57
    182
    Paraesthesia
         subjects affected / exposed
    5 / 172 (2.91%)
    19 / 345 (5.51%)
         occurrences all number
    5
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 172 (13.37%)
    108 / 345 (31.30%)
         occurrences all number
    39
    325
    Leukopenia
         subjects affected / exposed
    2 / 172 (1.16%)
    113 / 345 (32.75%)
         occurrences all number
    9
    487
    Neutropenia
         subjects affected / exposed
    4 / 172 (2.33%)
    231 / 345 (66.96%)
         occurrences all number
    10
    1689
    Thrombocytopenia
         subjects affected / exposed
    0 / 172 (0.00%)
    51 / 345 (14.78%)
         occurrences all number
    0
    210
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    2 / 172 (1.16%)
    27 / 345 (7.83%)
         occurrences all number
    2
    44
    Vision blurred
         subjects affected / exposed
    3 / 172 (1.74%)
    23 / 345 (6.67%)
         occurrences all number
    3
    31
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    35 / 172 (20.35%)
    95 / 345 (27.54%)
         occurrences all number
    54
    242
    Abdominal pain
         subjects affected / exposed
    13 / 172 (7.56%)
    31 / 345 (8.99%)
         occurrences all number
    17
    43
    Abdominal pain upper
         subjects affected / exposed
    15 / 172 (8.72%)
    24 / 345 (6.96%)
         occurrences all number
    19
    33
    Constipation
         subjects affected / exposed
    29 / 172 (16.86%)
    77 / 345 (22.32%)
         occurrences all number
    34
    107
    Dry mouth
         subjects affected / exposed
    16 / 172 (9.30%)
    27 / 345 (7.83%)
         occurrences all number
    18
    28
    Dyspepsia
         subjects affected / exposed
    9 / 172 (5.23%)
    41 / 345 (11.88%)
         occurrences all number
    11
    58
    Nausea
         subjects affected / exposed
    51 / 172 (29.65%)
    126 / 345 (36.52%)
         occurrences all number
    62
    221
    Stomatitis
         subjects affected / exposed
    5 / 172 (2.91%)
    51 / 345 (14.78%)
         occurrences all number
    6
    140
    Vomiting
         subjects affected / exposed
    27 / 172 (15.70%)
    76 / 345 (22.03%)
         occurrences all number
    40
    150
    Abdominal distension
         subjects affected / exposed
    9 / 172 (5.23%)
    21 / 345 (6.09%)
         occurrences all number
    12
    27
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 172 (1.74%)
    23 / 345 (6.67%)
         occurrences all number
    3
    29
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    11 / 172 (6.40%)
    68 / 345 (19.71%)
         occurrences all number
    11
    73
    Pruritus
         subjects affected / exposed
    14 / 172 (8.14%)
    32 / 345 (9.28%)
         occurrences all number
    17
    43
    Rash
         subjects affected / exposed
    8 / 172 (4.65%)
    46 / 345 (13.33%)
         occurrences all number
    9
    61
    Dry skin
         subjects affected / exposed
    3 / 172 (1.74%)
    29 / 345 (8.41%)
         occurrences all number
    4
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 172 (24.42%)
    90 / 345 (26.09%)
         occurrences all number
    61
    186
    Back pain
         subjects affected / exposed
    32 / 172 (18.60%)
    65 / 345 (18.84%)
         occurrences all number
    46
    97
    Muscle spasms
         subjects affected / exposed
    12 / 172 (6.98%)
    35 / 345 (10.14%)
         occurrences all number
    15
    56
    Musculoskeletal chest pain
         subjects affected / exposed
    11 / 172 (6.40%)
    21 / 345 (6.09%)
         occurrences all number
    14
    27
    Myalgia
         subjects affected / exposed
    15 / 172 (8.72%)
    35 / 345 (10.14%)
         occurrences all number
    18
    51
    Pain in extremity
         subjects affected / exposed
    27 / 172 (15.70%)
    62 / 345 (17.97%)
         occurrences all number
    35
    89
    Bone pain
         subjects affected / exposed
    9 / 172 (5.23%)
    28 / 345 (8.12%)
         occurrences all number
    11
    45
    Neck pain
         subjects affected / exposed
    8 / 172 (4.65%)
    18 / 345 (5.22%)
         occurrences all number
    8
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 172 (8.14%)
    50 / 345 (14.49%)
         occurrences all number
    24
    81
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 172 (7.56%)
    46 / 345 (13.33%)
         occurrences all number
    23
    67
    Influenza
         subjects affected / exposed
    10 / 172 (5.81%)
    12 / 345 (3.48%)
         occurrences all number
    12
    19
    Urinary tract infection
         subjects affected / exposed
    14 / 172 (8.14%)
    38 / 345 (11.01%)
         occurrences all number
    19
    57
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 172 (10.47%)
    61 / 345 (17.68%)
         occurrences all number
    22
    86

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2014
    In protocol amendment 1, schedule of assessments was updated with ocular safety assessments procedures to newly enrolled lens grading evaluable participants to assess the potential risk of palbociclib-associated lens changes. In human pharmacokinetic data, included preliminary results from two clinical pharmacology studies of palbociclib. Clarified inclusion criteria #6 and exclusion criteria #4, 5 and 6 to address frequent questions from investigational sites. Added prohibition to take proton-pump inhibitors while receiving study drug. Clarified that routine safety assessments must continue if patient continues study treatment despite progression of disease.
    30 Sep 2014
    In protocol amendment 2, In schedule of activities, laboratory safety assessments: added prospective monitoring of hemoglobin A1c to characterize whether or not palbociclib affects glucose metabolism. Added clarification to the schedule of administration of fulvestrant and goserelin. Editorial changes made to differentiate between strong and moderate CYP3A nducers/inhibitors. Added clarification of adverse events follow-up procedure (telephone contact) at 28 calendar days after treatment discontinuation. Additional editorial changes made to clarify follow-up procedures for patients who discontinue treatment for reasons other than disease progression and for patients who discontinue treatment due to disease progression.
    20 Oct 2015
    In protocol amendment 3, in schedule of activities, added clarification that tumor assessments will be conducted as per local practice. In study design section, added clarification that the third-party core imaging lab will not performed any longer blinded independent central review of PFS data. The investigators will stop sending the imaging studies to the central lab. Added clarification that survival follow-up visists will be conducted every 3 months after approval of amendment 3.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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