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    Clinical Trial Results:
    A phase III trial evaluating the role of continuous letrozole versus intermittent letrozole following 4 to 6 years of prior adjuvant endocrine therapy for postmenopausal women with hormone-receptor positive, node-positive early stage breast cancer.

    Summary
    EudraCT number
    		 2007-001370-88
    Trial protocol
    		 SE   BE   HU   IT   DE   DK   GB   ES   SI   GR   AT   IE  
    Global end of trial date
    15 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2020
    First version publication date
    23 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IBCSG35-07/BIG1-07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00553410
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBCSG
    Sponsor organisation address
    Effingerstrasse 40, Bern, Switzerland, 3008
    Public contact
    IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 313899391, regulatoryoffice@ibcsg.org
    Scientific contact
    IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 313899391, regulatoryoffice@ibcsg.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
    15 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare continuous letrozole for five years with intermittent letrozole over a five year period for postmenopausal women who are disease-free following 4-6 years of prior adjuvant endocrine therapy with SERM(s) and/or AI(s) for endocrine-responsive, node-positive, operable breast cancer.
    Protection of trial subjects
    In compliance with GDPR. Adverse events were reported and in case of adverse events and treatment-related toxicities, management guidance was provided in the study protocol to treat trial subjects in adequately manner. The safety of the trial treatment was regularly reviewed by the IBCSG Data Safety Monitoring Committee (DSMC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 2007
    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
    United States: 40
    Country: Number of subjects enrolled
    United Kingdom: 322
    Country: Number of subjects enrolled
    Slovenia: 24
    Country: Number of subjects enrolled
    Spain: 271
    Country: Number of subjects enrolled
    Sweden: 209
    Country: Number of subjects enrolled
    Austria: 180
    Country: Number of subjects enrolled
    Belgium: 1029
    Country: Number of subjects enrolled
    Denmark: 441
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 291
    Country: Number of subjects enrolled
    Hungary: 155
    Country: Number of subjects enrolled
    Ireland: 111
    Country: Number of subjects enrolled
    Italy: 578
    Country: Number of subjects enrolled
    Japan: 192
    Country: Number of subjects enrolled
    Australia: 365
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Chile: 140
    Country: Number of subjects enrolled
    India: 16
    Country: Number of subjects enrolled
    Peru: 66
    Country: Number of subjects enrolled
    Russian Federation: 43
    Country: Number of subjects enrolled
    South Africa: 56
    Country: Number of subjects enrolled
    Switzerland: 318
    Worldwide total number of subjects
    4884
    EEA total number of subjects
    3641
    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)
    3303
    From 65 to 84 years
    1572
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was activated 8 November 2007. The first patient was enrolled on 5 December 2007 and the trial closed to accrual on 8 October 2012 with 4884 patients enrolled.

    Pre-assignment
    Screening details
    		 This trial used a web-based randomization system. Each Participating Group determined how its Participating Centers will access the randomization system, either through a Group Randomization Center, or directly from the Participating Center.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Continuous letrozole
    Arm description
    		 Continuous letrozole: 5 years continuously (2.5 mg Letrozole daily)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated tablet, oral use, 2.5 mg Letrozole daily for 5 years continuously

    Arm title
    		 Intermittent letrozole
    Arm description
    		 Intermittent letrozole: 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated tablet, oral use, 2.5 mg daily, 48 months over 5 yrs: 4 x 9 months (9 months followed by 3 months treatment-free interval in years 1-4, -> 36 months) plus 1 x 12 months in year 5 -> 48 months

    Number of subjects in period 1 [1]
    		Continuous letrozole Intermittent letrozole
    Started
    2426
    2425
    Completed
    2426
    2425
    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: Baseline analysis was conducted only for ITT population. The primary ITT analysis population was 4851 of 4884 enrolled patients, 33 patients were excluded from the ITT population. Those were patients who immediately withdrew consent prior to treatment initiation and declined all participation, patients determined to be without adequate documentation of informed consent, and/or patients at a participating centre determined not to be compliant with protocol procedures.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Continuous letrozole
    Reporting group description
    		 Continuous letrozole: 5 years continuously (2.5 mg Letrozole daily)

    Reporting group title
    Intermittent letrozole
    Reporting group description
    		 Intermittent letrozole: 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months

    Reporting group values
    		 Continuous letrozole Intermittent letrozole Total
    Number of subjects
    		 2426 2425 4851
    Age categorical
    Units: Subjects
        <55
    		 688 671 1359
        55-59
    		 504 496 1000
        60-64
    		 451 471 922
        65-69
    		 400 375 775
        70+
    		 383 412 795
    Gender categorical
    Units: Subjects
        Female
    		 2426 2425 4851
        Male
    		 0 0 0
    Race/Ethnicity
    Units: Subjects
        White/Caucasian
    		 2199 2210 4409
        Black
    		 10 9 19
        Asian
    		 119 122 241
        Other
    		 97 83 180
        Unknown
    		 1 1 2
    Region of Enrollment
    Units: Subjects
        Hungary
    		 78 76 154
        United States
    		 21 19 40
        Japan
    		 93 98 191
        United Kingdom
    		 160 162 322
        Switzerland
    		 159 158 317
        India
    		 8 8 16
        Russia
    		 21 21 42
        Spain
    		 133 133 266
        New Zealand
    		 10 9 19
        Austria
    		 88 92 180
        Sweden
    		 104 105 209
        Belgium
    		 501 510 1011
        Denmark
    		 222 218 440
        Italy
    		 287 291 578
        South Africa
    		 28 28 56
        Australia
    		 182 171 353
        Chile
    		 70 70 140
        France
    		 14 16 30
        Peru
    		 33 31 64
        Germany
    		 146 143 289
        Slovenja
    		 12 12 24
        Ireland
    		 56 54 110

    End points

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    End points reporting groups
    Reporting group title
    Continuous letrozole
    Reporting group description
    		 Continuous letrozole: 5 years continuously (2.5 mg Letrozole daily)

    Reporting group title
    Intermittent letrozole
    Reporting group description
    		 Intermittent letrozole: 48 months over 5 yrs: 4 x 9 months (9 mo followed by 3 mo treatment-free interval in yrs 1-4, -> 36 mo) plus 1 x 12 mo in yr 5 -> 48 months

    Primary: Disease-free Survival (DFS)

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    End point title
    		 Disease-free Survival (DFS)
    End point description
    Duration of time from randomization to the first indication of the following events: invasive recurrence at local (including recurrence restricted to the breast after breast conserving treatment), regional or distant sites; a new invasive cancer in the contralateral breast; any second (non-breast) invasive malignancy; or a death without prior cancer event. Appearance of DCIS or LCIS either in the ipsilateral or in the contralateral breast was not be considered as an event for DFS. In the absence of an event, DFS was censored at the date of last follow-up visit.
    End point type
    Primary
    End point timeframe
    5-year estimates, reported at a median follow-up of 60 months
    End point values
    		 Continuous letrozole Intermittent letrozole
    Number of subjects analysed
    2426
    2425
    Units: Percentage of patients
        number (confidence interval 95%)
    87.5 (86.0 to 88.8)
    85.8 (84.2 to 87.2)
    Statistical analysis title
    		 Statistical analysis primary endpoint
    Statistical analysis description
    The primary endpoint is disease-free survival (DFS) and will be compared between treatment arms using a two-sided stratified logrank test with an overall experiment-wise alpha level equal to at most 0.05. Kaplan-Meier estimates of the DFS distributions will be calculated for each of the two treatment arms.
    Comparison groups
    Continuous letrozole v Intermittent letrozole
    Number of subjects included in analysis
    4851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.26

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Duration of time from randomization to death from any cause, or was censored at the date last known alive. (Note, for patients who withdrew consent or were lost to follow-up but follow-up for survival was possible through hospital or registry records, OS was censored at the date last known alive rather than date of last follow-up/withdrawn consent).
    End point type
    Secondary
    End point timeframe
    5-year estimates, reported at a median follow-up of 60 months
    End point values
    		 Continuous letrozole Intermittent letrozole
    Number of subjects analysed
    2426
    2425
    Units: Percentage of patients
        number (confidence interval 95%)
    93.7 (92.6 to 94.7)
    94.3 (93.2 to 95.2)
    Statistical analysis title
    		 Statistical analysis Overall Survival
    Comparison groups
    Continuous letrozole v Intermittent letrozole
    Number of subjects included in analysis
    4851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.06

    Secondary: Distant Recurrence-free Interval (DRFI)

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    End point title
    		 Distant Recurrence-free Interval (DRFI)
    End point description
    Duration of time from randomization to the first indication of invasive breast recurrence at a distant site. In the absence of an event, DRFI was censored at the date of last follow-up visit or date or death without distant recurrence.* *This endpoint replaced DDFS, which was specified in the protocol
    End point type
    Secondary
    End point timeframe
    5-year estimates, reported at a median follow-up of 60 months
    End point values
    		 Continuous letrozole Intermittent letrozole
    Number of subjects analysed
    2426
    2425
    Units: Percentage of patients
        number (confidence interval 95%)
    92.5 (91.3 to 93.5)
    93.2 (92.0 to 94.2)
    Statistical analysis title
    		 Statistical Analysis (DRFI)
    Comparison groups
    Continuous letrozole v Intermittent letrozole
    Number of subjects included in analysis
    4851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.09

    Secondary: Breast Cancer-free Interval

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    End point title
    		 Breast Cancer-free Interval
    End point description
    Duration of time from randomization to the first indication of the following events: invasive breast recurrence at local, regional or distant sites; a new invasive cancer in the contralateral breast (second non-breast malignancies are ignored). In the absence of an event, BCFI was censored at the date of last follow-up visit or date of death without prior breast cancer event.
    End point type
    Secondary
    End point timeframe
    5-year estimates, reported at a median follow-up of 60 months
    End point values
    		 Continuous letrozole Intermittent letrozole
    Number of subjects analysed
    2426
    2425
    Units: Percentage of patients
        number (confidence interval 95%)
    91.2 (89.9 to 92.3)
    90.9 (89.6 to 92.1)
    Statistical analysis title
    		 Statistical analysis BCFI
    Comparison groups
    Continuous letrozole v Intermittent letrozole
    Number of subjects included in analysis
    4851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.18

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    AEs graded according to NCI CTCAE V.3
    End point type
    Secondary
    End point timeframe
    Adverse event is defined as any untoward medical occurrence that occurs from the first dose of study medication until 30 days after final dose, regardless of whether it is considered related to a medication.
    End point values
    		 Continuous letrozole Intermittent letrozole
    Number of subjects analysed
    2411 [1]
    2417 [2]
    Units: Number of patients
    2411
    2417
    Notes
    [1] - 15 patients never started treatment
    [2] - 8 patients never started treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During or within 30 days after stopping study treatment
    Adverse event reporting additional description
    Adverse event is defined as any untoward medical occurrence that occurs from the first dose of study medication until 30 days after final dose, regardless of whether it is considered related to a medication. Any known untoward event that occurs subsequent to the adverse event reporting period that the investigator assesses as possibly related to t
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    V.3
    Reporting groups
    Reporting group title
    Continuous Letrozole
    Reporting group description
    		 15 pts never started treatment

    Reporting group title
    Intermittent Letrozole
    Reporting group description
    		 8 patients never started treatment

    Serious adverse events
    		 Continuous Letrozole Intermittent Letrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    121 / 2411 (5.02%)
    116 / 2417 (4.80%)
         number of deaths (all causes)
    38
    44
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mixed Mullerian tumor
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Carotid Stenosis
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis (R Calf)
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis and Pulmonary Embolism
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 2411 (0.08%)
    2 / 2417 (0.08%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis (Arteria Poplitea)
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Angioedema
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bilateral Ovarian Cysts
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian Cyst (Left)
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Bleeding
         subjects affected / exposed
    2 / 2411 (0.08%)
    4 / 2417 (0.17%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Dryness
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Bleeding (Restored Ovarian Function)
         subjects affected / exposed
    5 / 2411 (0.21%)
    13 / 2417 (0.54%)
         occurrences causally related to treatment / all
    5 / 5
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Edema
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    2 / 2411 (0.08%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia (Pacemaker Implantation)
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asymptomatic Subepicardial Ischemia and LVEF Reduction
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Ischemia
         subjects affected / exposed
    2 / 2411 (0.08%)
    3 / 2417 (0.12%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart Failure
         subjects affected / exposed
    2 / 2411 (0.08%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 2411 (0.04%)
    3 / 2417 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardio respiratory arrest
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Anxiety
         subjects affected / exposed
    1 / 2411 (0.04%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome requiring surgery
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    10 / 2411 (0.41%)
    8 / 2417 (0.33%)
         occurrences causally related to treatment / all
    12 / 12
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusion
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    7 / 2411 (0.29%)
    5 / 2417 (0.21%)
         occurrences causally related to treatment / all
    10 / 10
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory Impairment
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood alteration
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychosis
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe depression with suicidal ideation
         subjects affected / exposed
    1 / 2411 (0.04%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 2411 (0.04%)
    2 / 2417 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischemic Attack
         subjects affected / exposed
    3 / 2411 (0.12%)
    3 / 2417 (0.12%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 2411 (0.04%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden deafness
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 2411 (0.08%)
    2 / 2417 (0.08%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Esophagitis
         subjects affected / exposed
    1 / 2411 (0.04%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhagic gastritis
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria with itching
         subjects affected / exposed
    2 / 2411 (0.08%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urosepsis
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 2411 (0.00%)
    3 / 2417 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone fracture
         subjects affected / exposed
    56 / 2411 (2.32%)
    46 / 2417 (1.90%)
         occurrences causally related to treatment / all
    58 / 58
    48 / 48
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and head pain
         subjects affected / exposed
    0 / 2411 (0.00%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 2411 (0.08%)
    1 / 2417 (0.04%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polytrauma
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoarthrosis (L Humerus)
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    1 / 2411 (0.04%)
    0 / 2417 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Continuous Letrozole Intermittent Letrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2340 / 2411 (97.06%)
    2282 / 2417 (94.41%)
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    228 / 2411 (9.46%)
    207 / 2417 (8.56%)
         occurrences all number
    228
    207
    Thrombosis/embolism (vascular access-related)
         subjects affected / exposed
    29 / 2411 (1.20%)
    31 / 2417 (1.28%)
         occurrences all number
    29
    31
    Vascular disorders
    Hot flashes/flushes
         subjects affected / exposed
    1313 / 2411 (54.46%)
    1281 / 2417 (53.00%)
         occurrences all number
    1313
    1281
    Hypertension
         subjects affected / exposed
    1068 / 2411 (44.30%)
    1090 / 2417 (45.10%)
         occurrences all number
    1068
    1090
    Cardiac disorders
    Cardiac-ischemia/infarction
         subjects affected / exposed
    37 / 2411 (1.53%)
    48 / 2417 (1.99%)
         occurrences all number
    37
    48
    Nervous system disorders
    Hemorrhage, CNS
         subjects affected / exposed
    11 / 2411 (0.46%)
    13 / 2417 (0.54%)
         occurrences all number
    11
    13
    CNS cerebrovascular ischemia
         subjects affected / exposed
    42 / 2411 (1.74%)
    36 / 2417 (1.49%)
         occurrences all number
    42
    36
    General disorders and administration site conditions
    Fatigue (asthenia, lethargy, malaise)
         subjects affected / exposed
    1091 / 2411 (45.25%)
    1013 / 2417 (41.91%)
         occurrences all number
    1091
    1013
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1053 / 2411 (43.67%)
    1017 / 2417 (42.08%)
         occurrences all number
    1053
    1017
    Mood alteration - depression
         subjects affected / exposed
    833 / 2411 (34.55%)
    832 / 2417 (34.42%)
         occurrences all number
    833
    832
    Musculoskeletal and connective tissue disorders
    Osteoporosis
         subjects affected / exposed
    1150 / 2411 (47.70%)
    1153 / 2417 (47.70%)
         occurrences all number
    1150
    1153
    Pain - Bone
         subjects affected / exposed
    702 / 2411 (29.12%)
    671 / 2417 (27.76%)
         occurrences all number
    702
    671
    Pain - Joint
         subjects affected / exposed
    1664 / 2411 (69.02%)
    1599 / 2417 (66.16%)
         occurrences all number
    1664
    1599
    Pain - Muscle
         subjects affected / exposed
    906 / 2411 (37.58%)
    882 / 2417 (36.49%)
         occurrences all number
    906
    882

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30967649
    http://www.ncbi.nlm.nih.gov/pubmed/29158011
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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