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    Clinical Trial Results:
    A Randomized, Double Blind, Multi-center Study to Compare the Efficacy and Tolerability of Fulvestrant (FASLODEX™) vs Exemestane (AROMASIN™) in Postmenopausal Women with Hormone Receptor-Positive Advanced Breast Cancer with Disease Progression after Prior Non-Steroidal Aromatase Inhibitor (AI) Therapy

    Summary
    EudraCT number
    2004-000727-15
    Trial protocol
    HU  
    Global end of trial date
    30 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Aug 2017
    First version publication date
    05 Aug 2017
    Other versions
    Summary report(s)
    PDF of the article summarizing the results

    Trial information

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    Trial identification
    Sponsor protocol code
    D6697C00048 - 9238IL/0048
    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 (0)7585404954, jasmine.lichfield@astrazeneca.com
    Scientific contact
    Jasmine Lichfield, AstraZeneca, 44 (0)7585404954, 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
    30 Jun 2006
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2006
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of FASLODEX™ vs AROMASIN™ in postmenopausal women to see whether one drug will be more effective than the other in preventing the growth of cancer cells and also to see whether one drug will be better tolerated than the other.
    Protection of trial subjects
    An IDMC was implemented.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Aug 2003
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 44
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 190
    Country: Number of subjects enrolled
    Argentina: 53
    Country: Number of subjects enrolled
    Belgium: 51
    Country: Number of subjects enrolled
    Brazil: 88
    Country: Number of subjects enrolled
    Canada: 102
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Russian Federation: 34
    Worldwide total number of subjects
    759
    EEA total number of subjects
    245
    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)
    424
    From 65 to 84 years
    322
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment occurred between 5th August 2003 and 10th November 2005 in hospitals, clinics and offices across several countries.

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    759
    Number of subjects completed
    693

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    screening failure - not randomised: 66
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fulvestrant
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    FASLODEX
    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
    Exemestane
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    AROMASIN
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25mg, once daily, po

    Number of subjects in period 1 [1]
    Fulvestrant Exemestane
    Started
    351
    342
    Completed
    351
    342
    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 worldwide number enrolled into the trial (759) is all patients enrolled into screening, whereas the baseline period number (693) is those who were enrolled and randomized. The 66 patients who failed screening due to ineligibility are removed from this period.
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fulvestrant
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Fulvestrant
    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
    Exemestane
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25mg, once daily, po

    Number of subjects in period 2
    Fulvestrant Exemestane
    Started
    351
    342
    Completed
    119
    118
    Not completed
    232
    224
         information not collected
    232
    224

    Baseline characteristics

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

    Reporting group title
    Exemestane
    Reporting group description
    -

    Reporting group values
    Fulvestrant Exemestane Total
    Number of subjects
    351 342 693
    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)
    189 194 383
        From 65-84 years
    156 141 297
        85 years and over
    6 7 13
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    63.2 ± 10.96 63 ± 11.03 -
    Gender Categorical
    Units: Subjects
        Female
    351 342 693
    Race
    Units: Subjects
        Caucasian
    313 312 625
        Black
    11 13 24
        Oriental
    4 4 8
        Other
    23 13 36
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (ITT population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients

    Subject analysis sets values
    Full Analysis Set (ITT population)
    Number of subjects
    693
    Age Categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    383
        From 65-84 years
    297
        85 years and over
    13
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    63.1 ± 10.99
    Gender Categorical
    Units: Subjects
        Female
    693
    Race
    Units: Subjects
        Caucasian
    625
        Black
    24
        Oriental
    8
        Other
    36

    End points

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

    Reporting group title
    Exemestane
    Reporting group description
    -
    Reporting group title
    Fulvestrant
    Reporting group description
    -

    Reporting group title
    Exemestane
    Reporting group description
    -

    Subject analysis set title
    Full Analysis Set (ITT population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients

    Primary: Time to progression

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    End point title
    Time to progression
    End point description
    Time from randomisation to the earliest evidence of disease progression, or death from any cause.
    End point type
    Primary
    End point timeframe
    Time from randomisation to disease progression
    End point values
    Fulvestrant Exemestane
    Number of subjects analysed
    351
    342
    Units: Days
        median (not applicable)
    112 ± 0
    112 ± 0
    Statistical analysis title
    Log rank test for time to progression
    Statistical analysis description
    Log rank test (fitting treatment only) for time from randomisation to objective disease progression or death from any cause
    Comparison groups
    Fulvestrant v Exemestane
    Number of subjects included in analysis
    693
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.6531
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.963
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.819
         upper limit
    1.133
    Notes
    [1] - HR < 1 favours fulvestrant

    Secondary: Objective response rate

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    End point title
    Objective response rate
    End point description
    The number of patients with measurable disease at baseline who had a complete or partial objective response during the study.
    End point type
    Secondary
    End point timeframe
    Between randomisation and data cut off
    End point values
    Fulvestrant Exemestane
    Number of subjects analysed
    270 [2]
    270 [3]
    Units: Patients
    20
    18
    Notes
    [2] - Patients evaluable for response (measurable disease at baseline)
    [3] - Patients evaluable for response (measurable disease at baseline)
    Statistical analysis title
    Logistic regression of objective response rate
    Statistical analysis description
    Logisitic regression adjusting for treatment only
    Comparison groups
    Fulvestrant v Exemestane
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.7364
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.578
         upper limit
    2.186
    Notes
    [4] - OR >1 favours fulvestrant

    Secondary: Clinical benefit rate

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    End point title
    Clinical benefit rate
    End point description
    The number of patients with measurable disease who had a complete or partial objective response or stable disease for at least 24 weeks during the study
    End point type
    Secondary
    End point timeframe
    Between randomisation and data cut off
    End point values
    Fulvestrant Exemestane
    Number of subjects analysed
    270 [5]
    270 [6]
    Units: patients
    87
    85
    Notes
    [5] - Patients evaulable for response (measurable disease at baseline)
    [6] - Patients evaulable for response (measurable disease at baseline)
    Statistical analysis title
    Logisitic regression of clinical benefit rate
    Statistical analysis description
    Logistic regression adjusting for treatment only
    Comparison groups
    Fulvestrant v Exemestane
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.8534
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.487
    Notes
    [7] - OR > 1 favours fulvestrant

    Secondary: Quality of Life - Trial Outcome Index (TOI)

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    End point title
    Quality of Life - Trial Outcome Index (TOI)
    End point description
    TOI measured at baseline and month 12 are summarised.
    End point type
    Secondary
    End point timeframe
    From randomisation to data cut off
    End point values
    Fulvestrant Fulvestrant Exemestane Exemestane
    Number of subjects analysed
    290 [8]
    290 [9]
    280
    280 [10]
    Units: none
        arithmetic mean (standard deviation)
    52.1 ± 10.67
    51.4 ± 7.98
    53.1 ± 9.99
    54 ± 10.31
    Notes
    [8] - number at baseline was 291
    [9] - number at month 12 was 40
    [10] - number at month 12 was 42
    Statistical analysis title
    Repeated measures analysis of TOI over time
    Statistical analysis description
    A linear mixed model using baseline score as a covariate.
    Comparison groups
    Fulvestrant v Exemestane
    Number of subjects included in analysis
    570
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [11]
    P-value
    = 0.322
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.5506
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5405
         upper limit
    1.6417
    Notes
    [11] - A positive treatment difference favours fulvestrant.

    Secondary: Functional Assessment of Cancer Therapy - Endocrine system (FACT-ES)

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    End point title
    Functional Assessment of Cancer Therapy - Endocrine system (FACT-ES)
    End point description
    Baseline and month 12 data shown.
    End point type
    Secondary
    End point timeframe
    From randomisation to data cut off
    End point values
    Fulvestrant Fulvestrant Exemestane Exemestane
    Number of subjects analysed
    286 [12]
    286 [13]
    281
    281 [14]
    Units: none
        arithmetic mean (standard deviation)
    138.1 ± 20.44
    141 ± 20.86
    140.6 ± 20.93
    143.9 ± 19.58
    Notes
    [12] - number at baseline was 287
    [13] - number at month 12 was 42
    [14] - number at month 12 was 44
    Statistical analysis title
    Repeated measures analysis of FACT-ES over time
    Statistical analysis description
    A linear mixed model using baseline score as a covariate
    Comparison groups
    Fulvestrant v Exemestane
    Number of subjects included in analysis
    567
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [15]
    P-value
    = 0.7772
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.2795
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6597
         upper limit
    2.2187
    Notes
    [15] - A positive treament difference favours fulvestrant

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to 8 weeks after the last study treatment injection was administered or 30 days after the last study treament capsule was taken, whichever was longer.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Exemestane
    Reporting group description
    Exemestane

    Reporting group title
    Fulvestrant
    Reporting group description
    Fulvestrant

    Serious adverse events
    Exemestane Fulvestrant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 340 (12.35%)
    40 / 351 (11.40%)
         number of deaths (all causes)
    117
    119
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 340 (0.59%)
    2 / 351 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anticipatory anxiety
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         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
    Hip fracture
         subjects affected / exposed
    2 / 340 (0.59%)
    2 / 351 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (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 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 340 (0.29%)
    1 / 351 (0.28%)
         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
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischemia
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Palpitations
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         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 exacerbated
         subjects affected / exposed
    2 / 340 (0.59%)
    2 / 351 (0.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 340 (0.59%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 340 (0.88%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 340 (0.29%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 340 (0.59%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         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 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningeal disorder
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 340 (0.00%)
    3 / 351 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 340 (0.29%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 340 (0.00%)
    2 / 351 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    2 / 340 (0.59%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (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
    3 / 340 (0.88%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 340 (0.29%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         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
    1 / 340 (0.29%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 340 (0.29%)
    2 / 351 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 340 (0.00%)
    2 / 351 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 340 (0.29%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 340 (0.59%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Actinomycosis
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 340 (0.00%)
    1 / 351 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 340 (0.29%)
    0 / 351 (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
    Exemestane Fulvestrant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    298 / 340 (87.65%)
    307 / 351 (87.46%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    49 / 340 (14.41%)
    37 / 351 (10.54%)
         occurrences all number
    71
    48
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 340 (11.47%)
    33 / 351 (9.40%)
         occurrences all number
    53
    48
    Dyspnoea
         subjects affected / exposed
    28 / 340 (8.24%)
    30 / 351 (8.55%)
         occurrences all number
    33
    41
    Nervous system disorders
    Headache
         subjects affected / exposed
    41 / 340 (12.06%)
    42 / 351 (11.97%)
         occurrences all number
    66
    72
    Dizziness
         subjects affected / exposed
    27 / 340 (7.94%)
    22 / 351 (6.27%)
         occurrences all number
    37
    27
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    79 / 340 (23.24%)
    56 / 351 (15.95%)
         occurrences all number
    115
    85
    Asthenia
         subjects affected / exposed
    28 / 340 (8.24%)
    41 / 351 (11.68%)
         occurrences all number
    40
    60
    Injection site pain
         subjects affected / exposed
    31 / 340 (9.12%)
    33 / 351 (9.40%)
         occurrences all number
    52
    62
    Oedema peripheral
         subjects affected / exposed
    23 / 340 (6.76%)
    19 / 351 (5.41%)
         occurrences all number
    30
    26
    Pyrexia
         subjects affected / exposed
    15 / 340 (4.41%)
    19 / 351 (5.41%)
         occurrences all number
    18
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    28 / 340 (8.24%)
    21 / 351 (5.98%)
         occurrences all number
    33
    26
    Anxiety
         subjects affected / exposed
    19 / 340 (5.59%)
    19 / 351 (5.41%)
         occurrences all number
    26
    27
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    74 / 340 (21.76%)
    69 / 351 (19.66%)
         occurrences all number
    107
    112
    Diarrhoea
         subjects affected / exposed
    44 / 340 (12.94%)
    46 / 351 (13.11%)
         occurrences all number
    55
    63
    Vomiting
         subjects affected / exposed
    37 / 340 (10.88%)
    34 / 351 (9.69%)
         occurrences all number
    43
    48
    Constipation
         subjects affected / exposed
    28 / 340 (8.24%)
    31 / 351 (8.83%)
         occurrences all number
    33
    46
    Abdominal pain
         subjects affected / exposed
    13 / 340 (3.82%)
    20 / 351 (5.70%)
         occurrences all number
    16
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    49 / 340 (14.41%)
    49 / 351 (13.96%)
         occurrences all number
    85
    75
    Pain in extremity
         subjects affected / exposed
    43 / 340 (12.65%)
    30 / 351 (8.55%)
         occurrences all number
    63
    47
    Back pain
         subjects affected / exposed
    34 / 340 (10.00%)
    28 / 351 (7.98%)
         occurrences all number
    42
    42
    Bone pain
         subjects affected / exposed
    23 / 340 (6.76%)
    22 / 351 (6.27%)
         occurrences all number
    31
    41
    Myalgia
         subjects affected / exposed
    20 / 340 (5.88%)
    21 / 351 (5.98%)
         occurrences all number
    35
    28
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    32 / 340 (9.41%)
    33 / 351 (9.40%)
         occurrences all number
    36
    50
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 340 (4.71%)
    19 / 351 (5.41%)
         occurrences all number
    21
    27
    Urinary tract infection
         subjects affected / exposed
    12 / 340 (3.53%)
    19 / 351 (5.41%)
         occurrences all number
    20
    20
    Influenza
         subjects affected / exposed
    8 / 340 (2.35%)
    18 / 351 (5.13%)
         occurrences all number
    13
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2004
    Patients with bone lesions, lytic or mixed (lytic + sclerotic), in the absence of measurable disease per RECIST criteria, were made eligible to participate in the study. Clarification of following: - That either bone scans or skeletal surveys were to be performed at baseline for all patients, then every 4 months until progression for patients with any metastatic bone lesions at baseline. - Exclusion of patients with known brain or CNS metastases (Exclusion # 12). - Tumor assessments in accordance with RECIST criteria. - Addition of safety info for fulvestrant & exemestane. - Concomitant treatments permitted and prohibited. - Exclusion of intercurrent systemic anti cancer therapy after prior non-steroidal AI therapy. - Tumor assessment schedule for patients who withdrew for reasons other than progression. - QoL completion & removal of the 1-month post progression QoL completion time point. - Health care resource completion and timing of health care resource collection. - Exclusion laboratory values for ALT or AST (Exclusion #6). - Timing of AE collection. - AE reporting including serious adverse events. - Change to details of hormone assessments. - Timing of PK assessments
    31 Jul 2007
    To allow patients who were on study drug therapy at the time of final survival analysis to continue on their assigned study therapy and go into an open label extension phase. The extension phase allowed patients who are receiving benefit from study therapy to continue to receive study therapy after the time of final survival analysis. During the extension AstraZeneca only collected safety assessments (i.e. SAE’s and drug accountability data). Radiological assessments, haematology & clinical chemistry assessments were continued to be followed as normal standard level of care but data were not collected on the CRF.

    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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