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    Clinical Trial Results:
    Ensayo fase III aleatorizado, multicéntrico, abierto, de grupos paralelos para comparar la eficacia y tolerabilidad de Fulvestrant (Faslodex®) durante tres años en combinación con Anastrozol (Arimidex®) durante 5 años versus Anastrozol durante 5 años como tratamiento hormonal adyuvante en mujeres posmenopáusicas con cáncer de mama temprano y receptores hormonales positivos. A randomized, multicentral, phase III study of parallel groups to compare the efficiency and tolerance of Fulvestrant (Faslodex) administered for three years in combination with Anastrozol (Arimidex) for 5 years versus Anastrozol for 5 years as adjuvant hormonotherapy in postmenopausal women with early breast cancer and positive hormonal receptors.

    Summary
    EudraCT number
    		 2007-003417-14
    Trial protocol
    		 ES  
    Global end of trial date
    09 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2020
    First version publication date
    26 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GEICAM 2006-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00543127
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA)
    Sponsor organisation address
    Avenida de los Pirineos 7, San Sebastián de los Reyes / Madrid, Spain, 28703
    Public contact
    GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA), GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA), +34 916 592 870, inicio_ensayos@geicam.org
    Scientific contact
    GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA), GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA), +34 916 592 870, inicio_ensayos@geicam.org
    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
    02 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare free disease survival of patients treated with Fulvestrant for 3 years and anastrozol for 5 years vesus free disease survival of patients treated with anastrozol for 5 years.
    Protection of trial subjects
    Not applicable. It was not necessary to applied extra measures for protection of the subjects out of the good clinical practice environment.
    Background therapy
    		 Radiotherapy was allowed, and could be concomitantly administered within the study. The following restrictions applyed: 1. Concomitant treatments against cancer were not allowed. 2. Use of bisphosphonates to treat osteoporosis was allowed. 3. Administration of drugs containing sex hormones were not allowed. Use of a vaginal ring with estrogens or other topical preparations was allowed. Use of hormone antagonists or related drugs was not allowed. Use of topical applications, inhaled aerosols, eye drops, local injections, and mouthwashes (if not swallowed) containing corticosteroids or ketoconazole was allowed. 4. Patients receiving long-term anticoagulant treatment with warfarin could not participate 5. Patients who required anticoagulant treatment while receiving the trial treatment may receive low molecular weight heparin (LMWH) at the investigator’s discretion. 6. Patients who received anti-platelet agregants may have an increased bleeding risk from intramuscular injection. Any drug that was considered necessary for patient safety and wellbeing could be administered at the investigator’s discretion.
    Evidence for comparator
    		 Based on the results of multiple randomised studies, adjuvant treatment for hormone receptor positive breast cancer in postmenopausal women should include an aromatase inhibitor in order to decrease the risk of disease recurrence. Anastrozol for 5 years had shown to be superior in terms of efficacy and tolerability as compared to tamoxifen becoming a standard treatment in this group of patients (by the time of this study).
    Actual start date of recruitment
    28 Jan 2008
    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
    Spain: 870
    Worldwide total number of subjects
    870
    EEA total number of subjects
    870
    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)
    538
    From 65 to 84 years
    328
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 From January 2008 to June 2010, 872 patients were recruited in 53 Spanish sites belonging to GEICAM, Spanish Breast Cancer Group. For 2 patients the informed consent document could not be found and were not included in the analysis that was finally performed with 870 patients.

    Pre-assignment
    Screening details
    		 872 patients were recruited. For 2 patients the informed consent document could not be found and were not included in the analysis that was finally performed with 870 patients. 437 to control arm (Anastrozole) and 433 to experimental arm (Fulvestrant + Anastrozole). 18 patients (3 control arm + 15 experimental arm) never received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fulvestrant + Anastrozole
    Arm description
    		 Fulvestrant loading dose regimen consisted of two 5 ml intramuscular injections on day 0 (500 mg), 250 mg single injection on days 14 and 28, and 250 mg single injection every 28 days thereafter for 3 years plus Anastrozole 1 mg PO once daily for 5 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant loading dose regimen consisted of two 5 ml intramuscular injections on day 0 (500 mg), 250 mg single injection on days 14 and 28, and 250 mg single injection every 28 days thereafter for 3 years. Fulvestrant was supplied in a concentration of 250 mg in 5 ml in a prefilled syringe. Each fulvestrant dose was administered as a 250 mg dose, i.e. a 5 ml IM injection. Injections were administered by the IM route in the upper lateral quadrant of the buttock using an aseptic parenteral technique. The injection was administered slowly over approximately 1-2 minutes. After administration, investigator examined injection sites for local reactions. Patients was instructed to report to the investigator any complications that may occur.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozol 1 mg once daily orally for 5 years

    Arm title
    		 Anastrozole
    Arm description
    		 Anastrozole 1 mg will be administered orally as one tablet daily for 5 years.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozol 1 mg once daily orally for 5 years

    Number of subjects in period 1
    		Fulvestrant + Anastrozole Anastrozole
    Started
    433
    434
    Completed
    288
    319
    Not completed
    145
    118
         Consent withdrawn by subject
    48
    20
         Physician decision
    1
    -
         Adverse event, non-fatal
    21
    23
         Death
    3
    4
         Other
    12
    15
         Breast Cancer Relapse
    20
    25
         Transferred to other arm/group
    3
    -
         Second primary malignacy
    12
    9
         Lost to follow-up
    8
    18
         Protocol deviation
    2
    4
         Patients not treated
    15
    -
    Joined
    0
    3
         Transferred in from other group/arm
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fulvestrant + Anastrozole
    Reporting group description
    		 Fulvestrant loading dose regimen consisted of two 5 ml intramuscular injections on day 0 (500 mg), 250 mg single injection on days 14 and 28, and 250 mg single injection every 28 days thereafter for 3 years plus Anastrozole 1 mg PO once daily for 5 years

    Reporting group title
    Anastrozole
    Reporting group description
    		 Anastrozole 1 mg will be administered orally as one tablet daily for 5 years.

    Reporting group values
    		 Fulvestrant + Anastrozole Anastrozole Total
    Number of subjects
    		 433 437 870
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 267 271 538
        From 65-84 years
    		 164 164 328
        85 years and over
    		 2 2 4
    Age continuous
    Units: years
        median (full range (min-max))
    		 62 (40 to 86) 62 (44 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 433 437 870
        Male
    		 0 0 0
    Breast Surgery
    Units: Subjects
        Conservative
    		 303 310 613
        Mastectomy
    		 130 127 257
    Axillary surgery
    Units: Subjects
        Axillary dissection
    		 258 281 539
        Sentinel Node Biopsy
    		 174 155 329
        Unknown
    		 1 1 2
    Previous chemotherapy
    Units: Subjects
        Adjuvant
    		 256 261 517
        Neoadjuvant
    		 37 34 71
        Neoadjuvant + Adjuvant
    		 3 2 5
        None
    		 137 140 277
    Previous radiotherapy
    Units: Subjects
        Yes
    		 348 347 695
        No
    		 85 90 175
    Histopathologic type
    Units: Subjects
        Invasive Ductal Carcinoma
    		 337 346 683
        Invasive Lobular Carcinoma
    		 71 71 142
        Other
    		 25 20 45
    Histologic grade
    The grade of a breast cancer is a prognostic factor and is representative of the "aggressive potential" of the tumor. In a broad generalization, "low grade" cancers tend to be less aggressive than "high grade" cancers. There are 3 grades: Grade I tumors have a total score of 3-5, Grade II tumors have a total score of 6-7 and Grade III tumors have a total score of 8-9. Grade X is unknown result.
    Units: Subjects
        Grade 1
    		 88 82 170
        Grade 2
    		 216 235 451
        Grade 3
    		 94 83 177
        Grade X
    		 35 37 72
    Final diagnosis tumor size
    Using the Tumour Node Metastasis staging system (TNM) after surgery, the "T" plus a number (0 to 4) is used to describe the size of the tumor. The T0 means the lower size, and the T4 means the higher size. TX means unknown.
    Units: Subjects
        T1
    		 220 243 463
        T2
    		 189 179 368
        T3-T4
    		 22 14 36
        TX
    		 2 1 3
    Nodal status
    The "N" in the TNM staging stands for lymph nodes. NX: not evaluated. N0: No cancer was found / Only areas of cancer smaller than 0.2 mm. N1: The cancer has spread to 1 to 3 axillary lymph nodes and/or the internal mammary lymph nodes. N2: The cancer has spread to 4 to 9 axillary lymph nodes, or it has spread to the internal mammary lymph nodes, but not the axillary lymph nodes. N3: The cancer has spread to 10 or more axillary lymph nodes, or it has spread to the lymph nodes located under the clavicle, or collarbone. It may have also spread to the internal mammary lymph nodes.
    Units: Subjects
        N0
    		 214 200 414
        N1
    		 157 164 321
        N2
    		 42 52 94
        N3
    		 14 18 32
        NX
    		 6 3 9
    Tumor size
    Units: cm
        median (full range (min-max))
    		 2 (0.08 to 10) 2 (0.0 to 15) -

    End points

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    End points reporting groups
    Reporting group title
    Fulvestrant + Anastrozole
    Reporting group description
    		 Fulvestrant loading dose regimen consisted of two 5 ml intramuscular injections on day 0 (500 mg), 250 mg single injection on days 14 and 28, and 250 mg single injection every 28 days thereafter for 3 years plus Anastrozole 1 mg PO once daily for 5 years

    Reporting group title
    Anastrozole
    Reporting group description
    		 Anastrozole 1 mg will be administered orally as one tablet daily for 5 years.

    Primary: Disease Free Survival (DFS) Events

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    End point title
    		 Disease Free Survival (DFS) Events
    End point description
    Disease-free survival (DFS) has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. DFS event is defined as the evidence of local and/or distant recurrence, new primary breast tumour, or death from any cause.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    End point values
    		 Fulvestrant + Anastrozole Anastrozole
    Number of subjects analysed
    433
    437
    Units: Count of participants
        Breast Cancer Relapse
    35
    43
        Second primary breast cancer
    1
    3
        Death without evidence of relapse
    13
    16
        No DFS event
    384
    375
    Attachments
    		 DFS Kaplan-Meier
    Statistical analysis title
    		 Kaplan–Meier and log rank test
    Statistical analysis description
    Kaplan–Meier methods and log rank test
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.351
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox's proportional Hazard Ratio
    Statistical analysis description
    Cox's proportional hazards model
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.352
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.22

    Secondary: Breast Cancer Specific Survival (BCsS)

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    End point title
    		 Breast Cancer Specific Survival (BCsS)
    End point description
    BCsS events has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to BCsS in patients treated with anastrozole for 5 years. BCsS event is defined as the time to death for breast cancer.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Fulvestrant + Anastrozole Anastrozole
    Number of subjects analysed
    433
    437
    Units: Events
    17
    18
    Attachments
    		 BCsS KM
    Statistical analysis title
    		 Kaplan–Meier and log rank test
    Statistical analysis description
    Kaplan–Meier methods and log rank test
    Comparison groups
    Anastrozole v Fulvestrant + Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.966
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox's proportional Hazard Ratio
    Statistical analysis description
    Cox's proportional hazards model
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.966
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.91

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS event has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. OS event is defined as the death from any cause.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Fulvestrant + Anastrozole Anastrozole
    Number of subjects analysed
    433
    437
    Units: Events
    28
    34
    Attachments
    		 OS KM
    Statistical analysis title
    		 Kaplan–Meier and log rank test
    Statistical analysis description
    Kaplan–Meier methods and log rank test
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.558
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox's proportional Hazard Ratio
    Statistical analysis description
    Cox's proportional hazards model.
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.559
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.42

    Secondary: Time to Recurrence (TR)

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    End point title
    		 Time to Recurrence (TR)
    End point description
    TR event has been evaluated in patients treated with Fulvestrant for 3 years and Anastrozole for 5 years as compared to DFS in patients treated with anastrozole for 5 years. TR event is defined as the evidence of breast cancer recurrence (local and/or distant recurrence of breast cancer, does not include second primary malignancies or deaths from any cause).
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Fulvestrant + Anastrozole Anastrozole
    Number of subjects analysed
    433
    437
    Units: Events
    36
    46
    Attachments
    		 TTR KM
    Statistical analysis title
    		 Kaplan–Meier and log rank test
    Statistical analysis description
    Kaplan–Meier methods and log rank test
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.406
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox's proportional Hazard Ratio
    Statistical analysis description
    Cox's proportional hazards model.
    Comparison groups
    Fulvestrant + Anastrozole v Anastrozole
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.407
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.29

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) and Serious Adverse Events (SAEs) were recorded from the date informed consent was signed, during treatment period, and for up to 8 weeks after the last injection or up to 30 days after the last tablet.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTC
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Fulvestrant + Anastrozole
    Reporting group description
    		 Fulvestrant loading dose regimen consisted of two 5 ml intramuscular injections on day 0 (500 mg), 250 mg single injection on days 14 and 28, and 250 mg single injection every 28 days thereafter for 3 years plus Anastrozole 1 mg PO once daily for 5 years

    Reporting group title
    Anastrozole
    Reporting group description
    		 Anastrozole 1 mg will be administered orally as one tablet daily for 5 years.

    Serious adverse events
    		 Fulvestrant + Anastrozole Anastrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 415 (9.64%)
    61 / 437 (13.96%)
         number of deaths (all causes)
    28
    34
         number of deaths resulting from adverse events
    0
    2
    Vascular disorders
    Thrombosis/embolism (vascular access-related)
         subjects affected / exposed
    0 / 415 (0.00%)
    3 / 437 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Traffic accident
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microcalcification in breast
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary malignancy - possibly related to cancer treatment: uterine cervix cancer
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea (shortness of breath)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis/pulmonary infiltrates
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary/upper respiratory chest/thorax NOS pain
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angor
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiac ischemia/infarction
         subjects affected / exposed
    2 / 415 (0.48%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Conduction abnormality/atrioventricular heart block - av block-second degree mobitz type II
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular and nodal arrhythmia - atrial fibrilation
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular and nodal arrhythmia - sinus tachycardia
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Valvular heart disease
         subjects affected / exposed
    0 / 415 (0.00%)
    2 / 437 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilated cardiomyopathy
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (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
    CNS Cerebrovascular ischemia
         subjects affected / exposed
    1 / 415 (0.24%)
    4 / 437 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy: craneal - CN VI downward, inward movement of eye
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Hematoma
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemoglobin
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, CNS
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage, GI - colon
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hemorrhage GI - stomach
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhage/bleeding associated with surgery, intra-operative or post-operative
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lymphoblastic leukemia
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    4 / 415 (0.96%)
    4 / 437 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diarrhoea
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric diffuse
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastritis (including bile reflux gastritis)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal abdomen NOS pain
         subjects affected / exposed
    0 / 415 (0.00%)
    2 / 437 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus, GI (functional obstruction of bowel)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (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
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforation, GI - appendix
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer, GI - duodenum
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (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
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu-like syndrome
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 415 (0.48%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver dysfunction/failure (clinical)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatitis
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 415 (0.24%)
    3 / 437 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreas cancer
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (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
    Induration/fibrosis (skin and subcutaneous tissue)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction/extravasation changes
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanoma
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystocele
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 415 (0.00%)
    2 / 437 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary malignancy - possiby related to cancer treatment, specify: kidney cancer
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    2 / 415 (0.48%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    3 / 415 (0.72%)
    5 / 437 (1.14%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint pain
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthrosis
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection with grade 3 or 4 neutrophils (ANC <1.0 x 109/l) -upper respiratory - lung (pneumonia)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils - pulmonary/upper respiratory bronchus
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils - pulmonary/upper respiratory lung (pneumonia)
         subjects affected / exposed
    3 / 415 (0.72%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils - pulmonary/upper respiratory upper airway nos
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils - renal/genitourinary kidney
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils - renal/genitourinary urinary tract nos
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils - sexual/reproductive function vagina, vulva
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC or grade 1 or 2 neutrophils dermatology/skin skin (cellulitis)
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC - cardiovascular heart (endocarditis)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC - gastrointestinal appendix
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC - gastrointestinal dental-tooth
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC - pulmonary/upper respiratory lung (pneumonia)
         subjects affected / exposed
    1 / 415 (0.24%)
    2 / 437 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with unknown ANC - renal/genitourinary urinary tract nos
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Fulvestrant + Anastrozole Anastrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    192 / 415 (46.27%)
    197 / 437 (45.08%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary malignancy - possiby related to cancer treatment, specify: uterine cervix cancer
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Thrombosis/embolism (vascular access-related)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue (asthenia, lethargy, malaise)
         subjects affected / exposed
    30 / 415 (7.23%)
    11 / 437 (2.52%)
         occurrences all number
    30
    11
    Insomnia
         subjects affected / exposed
    3 / 415 (0.72%)
    0 / 437 (0.00%)
         occurrences all number
    3
    0
    Obesity
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Drug intolerance
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Sweating (diaphoresis)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Weight gain
         subjects affected / exposed
    12 / 415 (2.89%)
    8 / 437 (1.83%)
         occurrences all number
    12
    8
    Weight loss
         subjects affected / exposed
    1 / 415 (0.24%)
    4 / 437 (0.92%)
         occurrences all number
    1
    4
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever)
         subjects affected / exposed
    2 / 415 (0.48%)
    0 / 437 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Vaginal dryness
         subjects affected / exposed
    2 / 415 (0.48%)
    1 / 437 (0.23%)
         occurrences all number
    2
    1
    Investigations
    Albumin, serum-low (hypoalbuminemia)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    ALT, SGPT (Serum Glutamic Pyruvic Transaminase)
         subjects affected / exposed
    3 / 415 (0.72%)
    3 / 437 (0.69%)
         occurrences all number
    3
    3
    AST, SGOT (Serum Glutamic Oxaloacetic Transaminase)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Bilirubin (hyperbilirubinemia)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Cholesterol, serum-high (hypercholesterolemia)
         subjects affected / exposed
    9 / 415 (2.17%)
    10 / 437 (2.29%)
         occurrences all number
    9
    10
    GGT (Gamma-Glutamyl Transpeptidase)
         subjects affected / exposed
    1 / 415 (0.24%)
    4 / 437 (0.92%)
         occurrences all number
    1
    4
    Lactate dehydrogenase serum increased
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    LDL-cholesterol high
         subjects affected / exposed
    10 / 415 (2.41%)
    15 / 437 (3.43%)
         occurrences all number
    10
    15
    Triglyceride, serum-high (hypertriglyceridemia)
         subjects affected / exposed
    2 / 415 (0.48%)
    1 / 437 (0.23%)
         occurrences all number
    2
    1
    Cardiac disorders
    Supraventricular and nodal arrhythmia - atrial tachycardia/paroxysmal atrial tachycardia
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    4 / 415 (0.96%)
    8 / 437 (1.83%)
         occurrences all number
    4
    8
    Dilated cardiomyopathy
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences all number
    1
    1
    Mood alteration - depression
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences all number
    1
    1
    Neuropathy: sensory
         subjects affected / exposed
    1 / 415 (0.24%)
    2 / 437 (0.46%)
         occurrences all number
    1
    2
    Syncope (fainting)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    General pain NOS
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    3 / 415 (0.72%)
    3 / 437 (0.69%)
         occurrences all number
    3
    3
    Restless legs syndrome
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Leukocytes count decreased
         subjects affected / exposed
    1 / 415 (0.24%)
    4 / 437 (0.92%)
         occurrences all number
    1
    4
    Neutrophil/granulocyte count decreased
         subjects affected / exposed
    6 / 415 (1.45%)
    4 / 437 (0.92%)
         occurrences all number
    6
    4
    Platelet count decreased
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Anorexia nervosa
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Dry mouth/salivary gland (xerostomia)
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Mucositis/stomatitis (clinical exam) - oral cavity
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    4 / 415 (0.96%)
    0 / 437 (0.00%)
         occurrences all number
    4
    0
    Vomiting
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal abdomen NOS
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Flushing
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    2 / 415 (0.48%)
    1 / 437 (0.23%)
         occurrences all number
    2
    1
    Injection site reaction/extravasation changes
         subjects affected / exposed
    2 / 415 (0.48%)
    1 / 437 (0.23%)
         occurrences all number
    2
    1
    Nail changes
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Pruritus/itching
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Rash/desquamation
         subjects affected / exposed
    1 / 415 (0.24%)
    2 / 437 (0.46%)
         occurrences all number
    1
    2
    Rash: dermatitis associated with radiation - chemoradiation
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hot flush
         subjects affected / exposed
    21 / 415 (5.06%)
    15 / 437 (3.43%)
         occurrences all number
    21
    15
    Masculinization of female
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Pancreatic endocrine: glucose intolerance
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthritis (non-septic)
         subjects affected / exposed
    0 / 415 (0.00%)
    5 / 437 (1.14%)
         occurrences all number
    0
    5
    Fracture
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences all number
    1
    1
    Joint-function
         subjects affected / exposed
    0 / 415 (0.00%)
    2 / 437 (0.46%)
         occurrences all number
    0
    2
    Muscle weakness, generalized or specific area (not due to neuropathy) - whole body/generalized
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Myositis (inflamation/damage of muscle)
         subjects affected / exposed
    1 / 415 (0.24%)
    1 / 437 (0.23%)
         occurrences all number
    1
    1
    Osteoporosis
         subjects affected / exposed
    16 / 415 (3.86%)
    18 / 437 (4.12%)
         occurrences all number
    16
    18
    Arthrosis
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Dupuytren's contracture
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    2 / 415 (0.48%)
    2 / 437 (0.46%)
         occurrences all number
    2
    2
    Bone pain
         subjects affected / exposed
    27 / 415 (6.51%)
    13 / 437 (2.97%)
         occurrences all number
    27
    13
    Extremity-limb pain
         subjects affected / exposed
    2 / 415 (0.48%)
    3 / 437 (0.69%)
         occurrences all number
    2
    3
    Joint pain
         subjects affected / exposed
    57 / 415 (13.73%)
    64 / 437 (14.65%)
         occurrences all number
    57
    64
    Muscle pain
         subjects affected / exposed
    21 / 415 (5.06%)
    12 / 437 (2.75%)
         occurrences all number
    21
    12
    Neck pain
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Infection with normal ANC or grade 1 or 2 neutrophils - gastrointestinal dental-tooth
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Infection with normal ANC or grade 1 or 2 neutrophils - pulmonary/upper respiratory bronchus
         subjects affected / exposed
    0 / 415 (0.00%)
    1 / 437 (0.23%)
         occurrences all number
    0
    1
    Infection with unknown ANC - gastrointestinal oral cavity-gums (gingivitis)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Infection with unknown ANC - musculoskeletal muscle (infection myositis)
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0
    Infection with unknown ANC - sexual/reproductive function vagina
         subjects affected / exposed
    2 / 415 (0.48%)
    0 / 437 (0.00%)
         occurrences all number
    2
    0
    Breast
         subjects affected / exposed
    1 / 415 (0.24%)
    0 / 437 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2008
    Relevant Modification #1 dated 18/Sep/2008: Protocol Version 2 dated 13/Aug/2007 with amendment #1 dated 18/Sep/2008; the amendment was relevant because the inclusion criteria number 3 was updated to allow patients without node involvement (negative node) with a tumour size more than 1cm to be included, approved on 05/Nov/2008 by reference IRB and on 23/Nov/2008 by AEMPs.
    07 Sep 2009
    Relevant Modification #2 dated 15/Jun/2009: Protocol Version 2 dated 13/Aug/2007 with amendment #1 dated 18/Sep/2008 and amendment#2 dated 15/Jun/2009; the amendment was relevant because the inclusion criteria number 3 was updated to allow patients with stage IIIC invasive breast cancer (except patients with metastasis in infraclavicular nodes) to be included approved on 07/Sep/2009 by reference IRB and on 25/Sep/2009 by AEMPs.
    04 Apr 2011
    Relevant Modification #3 dated 03/May/2011: Protocol Version 2 dated 13/Aug/2007 with amendment #1 dated 18/Sep/2008, amendment #2 dated 15/Jun/2009 and amendment #3 dated 21/Feb/2011; the amendment was relevant because the recruitment was finished early and the justification was recorded in the new protocol version and an Adenda to Inform Consent Form (ICF) was generated to inform to all patient who were on treatment in that moment (Adenda Main ICF dated 21/Feb/2011) approved on 04/Apr/2011 by reference IRB and on 03/May/2011 by AEMPs.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Jun 2010
    On 29/Jun/2010 the recruitment was early interrupted with 872 enrolled patients because new information was published of other clinical trial about the treatment with fulvestrant in combination with anastrozole (FACT trial), and the financer decided to stop the study support.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No firm conclusions can be drawn because of the limited sample size achieved, due to the early stop of the trial.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31152327
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