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    Clinical Trial Results:
    A randomised, open-label, parallel group, multicentre, phase II study to compare the efficacy and tolerability of fulvestrant (FASLODEX) 500mg with anastrozole (ARIMIDEX) 1mg as first line hormonal treatment for postmenopausal women with hormone receptor positive advanced breast cancer.

    Summary
    EudraCT number
    2005-002868-28
    Trial protocol
    CZ   ES   GB   IT  
    Global end of trial date
    15 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jan 2018
    First version publication date
    26 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D6995C00006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom, SK10 4TG
    Public contact
    Jasmine Lichfield, AstraZeneca, 44 07585404954, jasmine.lichfield@astrazeneca.com
    Scientific contact
    Jasmine Lichfield, AstraZeneca, 44 07585404954, jasmine.lichfield@astrazeneca.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
    31 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the clinical benefit rate in patients treated with fulvestrant 500mg with patients treated with anastrozole 1mg
    Protection of trial subjects
    The protocol, relevant consent forms and patient information sheet were submitted for review to a recognised Independent Ethics Committee (IEC), covering each study site. Written approval identifying the Study Protocol version and consent document was obtained before patient recruitment commenced. Amendments to the Study Protocol were also submitted for written IEC approval before implementation. In North America this study was conducted under a Food and Drug Administration (FDA) investigational new drug (IND) application. In centres in North America the principal investigator provided an Institutional Review Board (IRB) with reports of any serious adverse drug reactions from any other study conducted with the investigational product. Progress reports and notifications of serious adverse drug reactions were provided to the IRB or IEC according to local regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Feb 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Bulgaria: 29
    Country: Number of subjects enrolled
    Czech Republic: 54
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Poland: 26
    Worldwide total number of subjects
    233
    EEA total number of subjects
    183
    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)
    93
    From 65 to 84 years
    134
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    233
    Number of subjects completed
    205

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    death: 1
    Reason: Number of subjects
    unknown: 2
    Reason: Number of subjects
    Consent withdrawn by subject: 4
    Reason: Number of subjects
    Protocol deviation: 20
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fulvestrant 500mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    FASLODEX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant 500mg (2 x 5mL IM injections) as a loading dose on Day 0, followed by 250mg (1 x 5 mL) on Day 14, Day 28 then monthy (28 +/- 3 days).

    Arm title
    Anastrozole 1mg
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    ARIMIDEX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole 1mg, once daily PO

    Number of subjects in period 1 [1]
    Fulvestrant 500mg Anastrozole 1mg
    Started
    102
    103
    Completed
    102
    103
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: the baseline period doesn’t contain data for patients not randomised so the numbers won’t match the world wide enrolment numbers
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fulvestrant 500mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    FASLODEX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant 500mg (2 x 5mL IM injections) as a loading dose on Day 0, followed by 250mg (1 x 5 mL) on Day 14, Day 28 then monthy (28 +/- 3 days).

    Arm title
    Anastrozole 1mg
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    ARIMIDEX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole 1mg, once daily PO

    Number of subjects in period 2
    Fulvestrant 500mg Anastrozole 1mg
    Started
    102
    103
    Completed
    23
    10
    Not completed
    79
    93
         death
    63
    74
         Consent withdrawn by subject
    16
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fulvestrant 500mg
    Reporting group description
    -

    Reporting group title
    Anastrozole 1mg
    Reporting group description
    -

    Reporting group values
    Fulvestrant 500mg Anastrozole 1mg Total
    Number of subjects
    102 103 205
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    45 40 85
        From 65-84 years
    54 60 114
        85 years and over
    3 3 6
    Age Continuous
    Units: years
        median (full range (min-max))
    66 (40 to 89) 68 (48 to 87) -
    Gender Categorical
    Units: Subjects
        Female
    102 103 205
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomised patients with no major protocol deviation

    Subject analysis set title
    Evaluable for response Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All randomised patients with measurable disease at baseline

    Subject analysis sets values
    Full Analysis Set Per Protocol Analysis Set Evaluable for response Set
    Number of subjects
    205
    198
    182
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    85
        From 65-84 years
    114
        85 years and over
    6
    Age Continuous
    Units: years
        median (full range (min-max))
    67 (40 to 89)
    Gender Categorical
    Units: Subjects
        Female
    205
    198
    182

    End points

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    End points reporting groups
    Reporting group title
    Fulvestrant 500mg
    Reporting group description
    -

    Reporting group title
    Anastrozole 1mg
    Reporting group description
    -
    Reporting group title
    Fulvestrant 500mg
    Reporting group description
    -

    Reporting group title
    Anastrozole 1mg
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomised patients with no major protocol deviation

    Subject analysis set title
    Evaluable for response Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All randomised patients with measurable disease at baseline

    Primary: Clinical Benefit Rate (CBR)

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    End point title
    Clinical Benefit Rate (CBR)
    End point description
    Patients with complete response, partial response or stable disease for at least 24 weeks.
    End point type
    Primary
    End point timeframe
    Randomisation to data cut off for primary analysis
    End point values
    Fulvestrant 500mg Anastrozole 1mg Full Analysis Set Per Protocol Analysis Set
    Number of subjects analysed
    102
    103
    205
    198
    Units: patients
    74
    69
    143
    139
    Statistical analysis title
    Logisitic regression analysis of CBR
    Statistical analysis description
    Logistic regression controlling for treatment only
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.386
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.302
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.717
         upper limit
    2.38
    Notes
    [1] - OR > 1 favours fulvestrant
    Statistical analysis title
    Logistic regression analysis of CBR
    Statistical analysis description
    Logistics regression analysis of CBR controlling for treatment only
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Per Protocol Analysis Set
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    = 0.276
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.404
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.763
         upper limit
    2.605
    Notes
    [2] - OR > 1 favours fulvestrant

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    patients with complete or partial response
    End point type
    Secondary
    End point timeframe
    randomsation to data cut off for the primary analysis
    End point values
    Fulvestrant 500mg Anastrozole 1mg Evaluable for response Set
    Number of subjects analysed
    89
    93
    182
    Units: patients
    32
    33
    65
    Statistical analysis title
    Logisitic regression of ORR
    Statistical analysis description
    Logisitic regression analysis of ORR controlling for treatment only.
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Evaluable for response Set
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.947
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.556
         upper limit
    1.874
    Notes
    [3] - OR > 1 favours fulvestrant

    Secondary: Time to Objective Disease Progression (TTP)

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    End point title
    Time to Objective Disease Progression (TTP)
    End point description
    time to objective disease progression or death from any cause
    End point type
    Secondary
    End point timeframe
    TTP from randomisation to data cut off for primary analysis
    End point values
    Fulvestrant 500mg Anastrozole 1mg Full Analysis Set
    Number of subjects analysed
    102 [4]
    103
    205
    Units: days
        median (full range (min-max))
    999999999 (999999999 to 999999999)
    381 (0 to 602)
    433 (0 to 604)
    Notes
    [4] - Median not reached
    Statistical analysis title
    Log rank analysis of TTP
    Statistical analysis description
    Log Rank analysis of TTP controlling for treatment only
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0496
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.6266
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3929
         upper limit
    0.9991
    Notes
    [5] - HR < 1 favours fulvestrant

    Secondary: Time to treatment failure (TTTF)

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    End point title
    Time to treatment failure (TTTF)
    End point description
    Time from randomisation to treatment discontinuation
    End point type
    Secondary
    End point timeframe
    Randomisation to data cut off for 75% treatment failure
    End point values
    Fulvestrant 500mg Anastrozole 1mg Full Analysis Set
    Number of subjects analysed
    102
    103
    205
    Units: days
        median (full range (min-max))
    536 (14 to 1401)
    387 (16 to 1369)
    457 (14 to 1401)
    Statistical analysis title
    Log Rank Analysis of TTTF
    Statistical analysis description
    Log Rank analysis of TTTF controlling for treatment only
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.05
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1
    Notes
    [6] - HR < 1 favours fulvestrant
    Statistical analysis title
    Cox regression analysif of TTTF
    Statistical analysis description
    Cox regression analysis of TTTF adjusting for baseline covariates
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.04
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    0.98
    Notes
    [7] - HR < 1 favours fulvestrant

    Secondary: Time to Progression (investigator assessed) (TTP)

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    End point title
    Time to Progression (investigator assessed) (TTP)
    End point description
    Time from randomisation to disease progression (investigator assessed) or death from any cause
    End point type
    Secondary
    End point timeframe
    Randomisation to data cut off for 75% TTTF analysis
    End point values
    Fulvestrant 500mg Anastrozole 1mg Full Analysis Set
    Number of subjects analysed
    102
    103
    205
    Units: days
        median (full range (min-max))
    712 (0 to 1387)
    400 (0 to 1369)
    518 (0 to 1387)
    Statistical analysis title
    Log Rank analysis of TTP
    Statistical analysis description
    Log rank analysis of TTP (investigator assessed) controlling for treatment only
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.01
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    0.92
    Notes
    [8] - HR < 1 favours fulvestrant
    Statistical analysis title
    Cox regression analysis of TTP
    Statistical analysis description
    Cox regression analysis of TTP (investigator assessed)controlling for baseline covariates
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.01
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    0.9
    Notes
    [9] - HR < 1 favours fulvestrant

    Post-hoc: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    time from randomisation to death (any cause)
    End point type
    Post-hoc
    End point timeframe
    randomisation to data cut off for 65% OS analysis
    End point values
    Fulvestrant 500mg Anastrozole 1mg Full Analysis Set
    Number of subjects analysed
    102
    103
    205
    Units: days
        median (full range (min-max))
    1647 (8 to 3060)
    1472 (16 to 2994)
    1519 (8 to 3060)
    Statistical analysis title
    Log Rank analysis of overall survival
    Statistical analysis description
    Log Rank analysis overall survival controlling for treatment only
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Post-hoc
    Analysis type
    superiority [10]
    P-value
    = 0.041
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.98
    Notes
    [10] - HR < 1 favours fulvestrant
    Statistical analysis title
    Cox regression analysis of OS
    Statistical analysis description
    Cox regression analysis of OS controlling for baseline covariates
    Comparison groups
    Fulvestrant 500mg v Anastrozole 1mg v Full Analysis Set
    Number of subjects included in analysis
    410
    Analysis specification
    Post-hoc
    Analysis type
    superiority [11]
    P-value
    = 0.126
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.08
    Notes
    [11] - HR < 1 favours fulvestrant

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious adverse events = randomisation upto the point of data cut off for the primary efficacy analysis. Serious adverse events = randomisation up to the point of data cut off for the 65% overall survival analysis
    Adverse event reporting additional description
    Non-serious adverse events are reported from randomisation upto the point of data cut off for the primary efficacy analysis (56 days after last injection and 30 days after last tablet). Serious adverse events are reported from randomisation up to the point of data cut off for the 65% overall survival analysis
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Fulvestrant 500mg
    Reporting group description
    Fulvestrant 500mg

    Reporting group title
    Anastrozole 1mg
    Reporting group description
    Anastrozole 1mg

    Serious adverse events
    Fulvestrant 500mg Anastrozole 1mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 101 (23.76%)
    22 / 103 (21.36%)
         number of deaths (all causes)
    63
    74
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to thorax
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoma
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrage
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Asthenia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary ostial stenosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         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
    Febrile neutropenia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphadenopathy
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         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
    Dyspnoea
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstrctive pulmonary disease
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacrimal disorder
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal haemrrohage
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Fulvestrant 500mg Anastrozole 1mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 101 (70.30%)
    70 / 103 (67.96%)
    Vascular disorders
    Hot flush
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    8 / 101 (7.92%)
    14 / 103 (13.59%)
         occurrences all number
    8
    15
    Hypertension
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    6 / 101 (5.94%)
    2 / 103 (1.94%)
         occurrences all number
    6
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    7 / 101 (6.93%)
    7 / 103 (6.80%)
         occurrences all number
    8
    7
    Cough
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    5 / 101 (4.95%)
    8 / 103 (7.77%)
         occurrences all number
    6
    9
    Nervous system disorders
    Dizziness
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 103 (5.83%)
         occurrences all number
    4
    6
    Headache
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    4 / 101 (3.96%)
    13 / 103 (12.62%)
         occurrences all number
    26
    16
    General disorders and administration site conditions
    Asthenia
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    8 / 101 (7.92%)
    8 / 103 (7.77%)
         occurrences all number
    14
    9
    Fatigue
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    1 / 101 (0.99%)
    8 / 103 (7.77%)
         occurrences all number
    1
    8
    Injection site pain
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    6 / 101 (5.94%)
    0 / 103 (0.00%)
         occurrences all number
    14
    0
    Gastrointestinal disorders
    Constipation
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    10 / 101 (9.90%)
    5 / 103 (4.85%)
         occurrences all number
    12
    5
    Diarrhoea
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    6 / 101 (5.94%)
    7 / 103 (6.80%)
         occurrences all number
    7
    7
    Vomiting
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    8 / 101 (7.92%)
    3 / 103 (2.91%)
         occurrences all number
    10
    4
    Nausea
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    10 / 101 (9.90%)
    7 / 103 (6.80%)
         occurrences all number
    10
    8
    Musculoskeletal and connective tissue disorders
    Bone pain
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    14 / 101 (13.86%)
    10 / 103 (9.71%)
         occurrences all number
    19
    23
    Arthralgia
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    10 / 101 (9.90%)
    8 / 103 (7.77%)
         occurrences all number
    14
    8
    Myalgia
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    3 / 101 (2.97%)
    9 / 103 (8.74%)
         occurrences all number
    3
    10
    Infections and infestations
    Influenza
    alternative dictionary used: MedDRA 10.1
         subjects affected / exposed
    1 / 101 (0.99%)
    6 / 103 (5.83%)
         occurrences all number
    1
    6

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2006
    Additional detail added regarding the exclusion of previously irradiated lesions from the analysis, as the effects of radiotherapy on tumours may manifest more than 6 weeks after completion of radiotherapy. Therefore inclusion of previously irradiated lesions in the analysis may have impacted the primary outcome variable of CBR. Also added further detail around concomitant use of vaginal creams and vaginal rings during the study. New evidence had come to light regarding the significance of the systemic absorption of oestrogens from topical vaginal preparations used in the treatment of menopausal symptoms (atrophic vaginitis) in patients taking AIs (Kendall et al 2006). The authors were of the opinion that the use of topical vaginal oestrogen-containing creams is contraindicated in patients taking AIs. On this basis, and also because the use of these creams had the potential to bias the study against the AI arm, the study restrictions were clarified to specifically preclude the use of oestrogen-containing vaginal creams or other oestrogen containing topical preparations. However given the distressing nature of atrophic vaginitis, it was felt necessary from an ethical point of view to allow the use of controlled-release oestrogen containing vaginal rings (e.g., Estring®), as a last resort only, pending any updated advice, and only at the discretion of the investigator.
    12 Apr 2010
    At the DCO for the primary analysis, patients on fulvestrant 500 mg had a 60% longer TTP compared to patients on anastrozole 1 mg. The data maturity in terms of the proportion of patients with progression events was approximately 30%. A more mature analysis, planned for when approximately 75% of patients had discontinued study treatment, allowed a more meaningful interpretation of this secondary endpoint. Since patients were not followed within the study according to formal scheduled RECIST assessments from the time of primary DCO onwards, a “time to treatment failure” (TTF) analysis was planned where treatment failure was determined according to the investigator’s opinion. This amendment also clarified the timing for the final analysis, and also documented that, for subjects still on study treatment, only serious adverse event data would be collected following the final analysis.
    07 Feb 2011
    Following a statistically significant benefit (time to progression hazard ratio = 0.66, 95% confidence interval (0.47, 0.92), p=0.01) in favour of fulvestrant, seen in the follow-up analysis of time to progression (TTP), it was decided to amend the protocol to investigate if the benefit observed for TTP translates into an overall survival (OS) benefit. The amendment covered the collection of OS data and detailed the performance of an OS analysis. It clarified that the “time to treatment failure analysis” (TTF) was not the final analysis for this study.
    03 Dec 2013
    The amendment covered the collection of overall survival (OS) data and described the change in timing for the final OS analysis. Significant decline in rate of death had been observed during the later stages of overall survival follow-up. This rate had become very unpredictable as the CSP amendment 3 was looking for events in a small group of patients. It was possible that 75% deaths would not be reached for several years, which was not considered a reasonable timeframe for obtaining information on OS. Performing the analysis at approximately 65% rather than 75% maturity did not make a large difference to the outcome, in terms of the largest observed HR which would achieve statistical significance (p<0.05); 0.71 and 0.73 for 65% and 75% respectively.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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