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    Clinical Trial Results:
    Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy

    Summary
    EudraCT number
    2004-000193-31
    Trial protocol
    GB  
    Global end of trial date

    Results information
    Results version number
    v1
    This version publication date
    27 Feb 2021
    First version publication date
    27 Feb 2021
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    PR08
    Additional study identifiers
    ISRCTN number
    ISRCTN78818544
    US NCT number
    NCT00268476
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    CTA: 20363/0404/001, MREC: 04/MRE07/35, Previous IRAS (Minimal Data Set): 31586
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E6BT
    Public contact
    STAMPEDE Trial Team, MRCCTU at UCL, adrian.cook@ucl.ac.uk
    Scientific contact
    STAMPEDE Trial Team, MRCCTU at UCL, 44 76704700, adrian.cook@ucl.ac.uk
    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
    Interim
    Date of interim/final analysis
    13 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This study aims to look at how to improve the way in which prostate cancer is currently managed i.e. by adding new treatments to the standard of care, whether it can enable men to live longer or, by modifying the type of hormone therapy, live at least as long and enjoy a better quality of life. The principal research question for most arms is whether the treatment concerned improves overall survival; however some comparisons such as metformin are being looked at for other reasons.
    Protection of trial subjects
    In routine care
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Oct 2004
    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 Kingdom: 11643
    Country: Number of subjects enrolled
    Switzerland: 95
    Worldwide total number of subjects
    11738
    EEA total number of subjects
    0
    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)
    4030
    From 65 to 84 years
    7683
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    First patient randomised 17Oct2005

    Pre-assignment
    Screening details
    Screening data not available centrally

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A (SOC for B,C,E comparisons)
    Arm description
    Reference patients for A vs B, C , E
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Arm B
    Arm description
    Zoledronic acid
    Arm type
    Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    4mg at six 3-weekly cycles, then 4-weekly until 2 years

    Arm title
    Arm C
    Arm description
    Docetaxel
    Arm type
    Experimental

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75mg/m2 for six 3-weekly cycles

    Arm title
    Arm E
    Arm description
    Zoledronic Acid and Docetaxel
    Arm type
    Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    4mg at six 3-weekly cycles, then 4-weekly until 2 years

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    75mg/m2 for six 3-weekly cycles

    Arm title
    Arm A (SOC for D,F comparisons)
    Arm description
    Reference patients for A vs D, F
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Arm D
    Arm description
    Celecoxib
    Arm type
    Experimental

    Investigational medicinal product name
    Celecoxib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400mg twice a day for 1 year

    Arm title
    Arm F
    Arm description
    Zoledronic Acid and Celecoxib
    Arm type
    Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous use
    Dosage and administration details
    4mg at six 3-weekly cycles, then 4-weekly until 2 years

    Investigational medicinal product name
    Celecoxib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400mg twice a day for 1 year

    Number of subjects in period 1 [1]
    Arm A (SOC for B,C,E comparisons) Arm B Arm C Arm E Arm A (SOC for D,F comparisons) Arm D Arm F
    Started
    1184
    593
    592
    593
    622
    312
    311
    Completed
    1184
    593
    592
    593
    622
    312
    311
    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: Trial arms are reported as each arm closes. Control patients (Arm A) are contemporaneously matched to experimental arms.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (SOC for B,C,E comparisons)
    Reporting group description
    Reference patients for A vs B, C , E

    Reporting group title
    Arm B
    Reporting group description
    Zoledronic acid

    Reporting group title
    Arm C
    Reporting group description
    Docetaxel

    Reporting group title
    Arm E
    Reporting group description
    Zoledronic Acid and Docetaxel

    Reporting group title
    Arm A (SOC for D,F comparisons)
    Reporting group description
    Reference patients for A vs D, F

    Reporting group title
    Arm D
    Reporting group description
    Celecoxib

    Reporting group title
    Arm F
    Reporting group description
    Zoledronic Acid and Celecoxib

    Reporting group values
    Arm A (SOC for B,C,E comparisons) Arm B Arm C Arm E Arm A (SOC for D,F comparisons) Arm D Arm F Total
    Number of subjects
    1184 593 592 593 622 312 311 4207
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0
        Adults (18-64 years)
    521 265 270 252 294 139 146 1887
        From 65-84 years
    663 328 322 341 328 173 164 2319
        85 years and over
    0 0 0 0 0 0 1 1
    Gender categorical
    Units: Subjects
        Female
    0 0 0 0 0 0 0 0
        Male
    1184 593 592 593 622 312 311 4207
    Subject analysis sets

    Subject analysis set title
    Arm A (SOC for B,C,E comparisons)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Reference patients (ABCE comparison)

    Subject analysis set title
    Arm B (ZA)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Experimental group, AB comparison

    Subject analysis set title
    Arm C (doce)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Arm A vs C

    Subject analysis set title
    Arm E (doce+ZA)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Docetaxel and Zoledronic acid

    Subject analysis set title
    Arm A (SOC for D,F comparisons)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Reference patients (ADF comparisons)

    Subject analysis set title
    Arm D (cel)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Arm A vs D

    Subject analysis set title
    Arm F (cel+ZA)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Arm A vs F

    Subject analysis sets values
    Arm A (SOC for B,C,E comparisons) Arm B (ZA) Arm C (doce) Arm E (doce+ZA) Arm A (SOC for D,F comparisons) Arm D (cel) Arm F (cel+ZA)
    Number of subjects
    1184
    593
    592
    593
    622
    312
    311
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    521
    265
    270
    252
    294
    139
    146
        From 65-84 years
    663
    328
    322
    341
    328
    173
    164
        85 years and over
    0
    0
    0
    0
    0
    0
    1
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
    0
    0
    0
    0
        Male
    1184
    593
    592
    593
    622
    312
    311

    End points

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    End points reporting groups
    Reporting group title
    Arm A (SOC for B,C,E comparisons)
    Reporting group description
    Reference patients for A vs B, C , E

    Reporting group title
    Arm B
    Reporting group description
    Zoledronic acid

    Reporting group title
    Arm C
    Reporting group description
    Docetaxel

    Reporting group title
    Arm E
    Reporting group description
    Zoledronic Acid and Docetaxel

    Reporting group title
    Arm A (SOC for D,F comparisons)
    Reporting group description
    Reference patients for A vs D, F

    Reporting group title
    Arm D
    Reporting group description
    Celecoxib

    Reporting group title
    Arm F
    Reporting group description
    Zoledronic Acid and Celecoxib

    Subject analysis set title
    Arm A (SOC for B,C,E comparisons)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Reference patients (ABCE comparison)

    Subject analysis set title
    Arm B (ZA)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Experimental group, AB comparison

    Subject analysis set title
    Arm C (doce)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Arm A vs C

    Subject analysis set title
    Arm E (doce+ZA)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Docetaxel and Zoledronic acid

    Subject analysis set title
    Arm A (SOC for D,F comparisons)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Reference patients (ADF comparisons)

    Subject analysis set title
    Arm D (cel)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Arm A vs D

    Subject analysis set title
    Arm F (cel+ZA)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Arm A vs F

    Primary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Primary
    End point timeframe
    Event driven analysis
    End point values
    Arm A (SOC for B,C,E comparisons) Arm B (ZA) Arm C (doce) Arm E (doce+ZA) Arm A (SOC for D,F comparisons) Arm D (cel) Arm F (cel+ZA)
    Number of subjects analysed
    1184
    593
    592
    593
    622
    312
    311
    Units: Patients
        Died
    415
    201
    175
    187
    303
    143
    138
    Statistical analysis title
    Zoledronic Acid vs SOC
    Comparison groups
    Arm A (SOC for B,C,E comparisons) v Arm B (ZA)
    Number of subjects included in analysis
    1777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.45
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.11
    Statistical analysis title
    Docetaxel vs SOC
    Comparison groups
    Arm A (SOC for B,C,E comparisons) v Arm C (doce)
    Number of subjects included in analysis
    1776
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    0.93
    Statistical analysis title
    Docetaxel+Zoledronic Acid vs SOC
    Comparison groups
    Arm A (SOC for B,C,E comparisons) v Arm E (doce+ZA)
    Number of subjects included in analysis
    1777
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.022
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    0.97
    Statistical analysis title
    Celecoxib vs SOC
    Comparison groups
    Arm D (cel) v Arm A (SOC for D,F comparisons)
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.847
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.2
    Statistical analysis title
    Celecoxib + Zoledronic acid vs SOC
    Comparison groups
    Arm A (SOC for D,F comparisons) v Arm F (cel+ZA)
    Number of subjects included in analysis
    933
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Events to March 4 2015 for A vs B,C,E comparisons Events to December 15 2015 for A vs D,F comparisons
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    SOC (Arm A, ABCE comparison)
    Reporting group description
    Reference patients, Arm A, randomised between A,B,C,E

    Reporting group title
    ZA (Arm B)
    Reporting group description
    Experimental patients, AB comparison

    Reporting group title
    Doce (Arm C)
    Reporting group description
    Arm C docetaxel patients

    Reporting group title
    Doce+ZA (Arm E)
    Reporting group description
    Docetaxel plus Zoledronic acid

    Reporting group title
    SOC (Arm A, ADF comparison)
    Reporting group description
    Reference patients, Arm A, randomised between A,D,F

    Reporting group title
    Celecoxib (Arm D)
    Reporting group description
    Experimental arm, celecoxib comparison

    Reporting group title
    Celecoxib + ZA
    Reporting group description
    (Arm F)

    Serious adverse events
    SOC (Arm A, ABCE comparison) ZA (Arm B) Doce (Arm C) Doce+ZA (Arm E) SOC (Arm A, ADF comparison) Celecoxib (Arm D) Celecoxib + ZA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    59 / 1184 (4.98%)
    30 / 593 (5.06%)
    126 / 592 (21.28%)
    134 / 593 (22.60%)
    35 / 622 (5.63%)
    15 / 312 (4.81%)
    33 / 311 (10.61%)
         number of deaths (all causes)
    415
    201
    175
    187
    303
    143
    138
         number of deaths resulting from adverse events
    0
    0
    1
    2
    0
    0
    0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    7 / 1184 (0.59%)
    4 / 593 (0.67%)
    5 / 592 (0.84%)
    5 / 593 (0.84%)
    5 / 622 (0.80%)
    2 / 312 (0.64%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
    1 / 5
    0 / 5
    0 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    Arrhythmia
         subjects affected / exposed
    2 / 1184 (0.17%)
    1 / 593 (0.17%)
    2 / 592 (0.34%)
    6 / 593 (1.01%)
    0 / 622 (0.00%)
    2 / 312 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    2 / 7
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    1 / 312 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 1184 (0.00%)
    2 / 593 (0.34%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 1184 (0.42%)
    3 / 593 (0.51%)
    2 / 592 (0.34%)
    2 / 593 (0.34%)
    1 / 622 (0.16%)
    1 / 312 (0.32%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
    1 / 2
    0 / 2
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 1184 (0.59%)
    3 / 593 (0.51%)
    77 / 592 (13.01%)
    65 / 593 (10.96%)
    4 / 622 (0.64%)
    0 / 312 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
    79 / 83
    66 / 73
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    3 / 592 (0.51%)
    9 / 593 (1.52%)
    1 / 622 (0.16%)
    0 / 312 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
    9 / 9
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 1184 (0.17%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    2 / 593 (0.34%)
    1 / 622 (0.16%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    4 / 592 (0.68%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    3 / 1184 (0.25%)
    2 / 593 (0.34%)
    6 / 592 (1.01%)
    17 / 593 (2.87%)
    2 / 622 (0.32%)
    0 / 312 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    5 / 6
    5 / 18
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 1184 (0.00%)
    1 / 593 (0.17%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 1184 (0.17%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    1 / 593 (0.17%)
    1 / 622 (0.16%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 1184 (0.17%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    2 / 593 (0.34%)
    2 / 622 (0.32%)
    1 / 312 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    8 / 592 (1.35%)
    4 / 593 (0.67%)
    1 / 622 (0.16%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    8 / 8
    4 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 1184 (0.34%)
    4 / 593 (0.67%)
    2 / 592 (0.34%)
    7 / 593 (1.18%)
    3 / 622 (0.48%)
    1 / 312 (0.32%)
    6 / 311 (1.93%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    2 / 2
    0 / 7
    0 / 3
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 1184 (0.25%)
    1 / 593 (0.17%)
    3 / 592 (0.51%)
    1 / 593 (0.17%)
    3 / 622 (0.48%)
    1 / 312 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    1 / 3
    0 / 1
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 1184 (0.42%)
    1 / 593 (0.17%)
    8 / 592 (1.35%)
    10 / 593 (1.69%)
    4 / 622 (0.64%)
    0 / 312 (0.00%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    5 / 8
    5 / 11
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    2 / 592 (0.34%)
    6 / 593 (1.01%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    3 / 7
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 1184 (0.17%)
    2 / 593 (0.34%)
    3 / 592 (0.51%)
    6 / 593 (1.01%)
    2 / 622 (0.32%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 3
    2 / 7
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    1 / 593 (0.17%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    2 / 1184 (0.17%)
    1 / 593 (0.17%)
    2 / 592 (0.34%)
    5 / 593 (0.84%)
    0 / 622 (0.00%)
    1 / 312 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 5
    0 / 5
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    1 / 593 (0.17%)
    1 / 622 (0.16%)
    1 / 312 (0.32%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    2 / 592 (0.34%)
    1 / 593 (0.17%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 1184 (0.34%)
    3 / 593 (0.51%)
    5 / 592 (0.84%)
    5 / 593 (0.84%)
    2 / 622 (0.32%)
    0 / 312 (0.00%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    4 / 6
    2 / 5
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Nail discolouration
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    1 / 593 (0.17%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 1184 (0.00%)
    1 / 593 (0.17%)
    1 / 592 (0.17%)
    2 / 593 (0.34%)
    0 / 622 (0.00%)
    2 / 312 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 3
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    5 / 1184 (0.42%)
    2 / 593 (0.34%)
    6 / 592 (1.01%)
    4 / 593 (0.67%)
    2 / 622 (0.32%)
    1 / 312 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    2 / 6
    0 / 5
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    4 / 1184 (0.34%)
    2 / 593 (0.34%)
    0 / 592 (0.00%)
    2 / 593 (0.34%)
    2 / 622 (0.32%)
    0 / 312 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 1184 (0.17%)
    2 / 593 (0.34%)
    0 / 592 (0.00%)
    3 / 593 (0.51%)
    2 / 622 (0.32%)
    0 / 312 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    4 / 1184 (0.34%)
    3 / 593 (0.51%)
    1 / 592 (0.17%)
    3 / 593 (0.51%)
    2 / 622 (0.32%)
    0 / 312 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
    0 / 3
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    1 / 312 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    1 / 312 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    3 / 1184 (0.25%)
    2 / 593 (0.34%)
    3 / 592 (0.51%)
    1 / 593 (0.17%)
    3 / 622 (0.48%)
    1 / 312 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 1184 (0.08%)
    1 / 593 (0.17%)
    0 / 592 (0.00%)
    1 / 593 (0.17%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Glucose tolerance decreased
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    1 / 593 (0.17%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorexia nervosa
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    1 / 593 (0.17%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 1184 (0.08%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    1 / 592 (0.17%)
    0 / 593 (0.00%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SOC (Arm A, ABCE comparison) ZA (Arm B) Doce (Arm C) Doce+ZA (Arm E) SOC (Arm A, ADF comparison) Celecoxib (Arm D) Celecoxib + ZA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1152 / 1184 (97.30%)
    579 / 593 (97.64%)
    571 / 592 (96.45%)
    560 / 593 (94.44%)
    605 / 622 (97.27%)
    292 / 312 (93.59%)
    297 / 311 (95.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    84 / 1184 (7.09%)
    50 / 593 (8.43%)
    44 / 592 (7.43%)
    30 / 593 (5.06%)
    35 / 622 (5.63%)
    39 / 312 (12.50%)
    27 / 311 (8.68%)
         occurrences all number
    129
    90
    74
    42
    47
    63
    43
    Hot flush
         subjects affected / exposed
    968 / 1184 (81.76%)
    462 / 593 (77.91%)
    454 / 592 (76.69%)
    442 / 593 (74.54%)
    495 / 622 (79.58%)
    229 / 312 (73.40%)
    222 / 311 (71.38%)
         occurrences all number
    5324
    2400
    2425
    2356
    2877
    1321
    1268
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    29 / 1184 (2.45%)
    38 / 593 (6.41%)
    49 / 592 (8.28%)
    70 / 593 (11.80%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences all number
    39
    51
    58
    84
    0
    0
    0
    Fatigue
         subjects affected / exposed
    632 / 1184 (53.38%)
    342 / 593 (57.67%)
    431 / 592 (72.80%)
    427 / 593 (72.01%)
    333 / 622 (53.54%)
    151 / 312 (48.40%)
    165 / 311 (53.05%)
         occurrences all number
    1999
    1144
    1616
    1607
    1080
    424
    536
    Oedema
         subjects affected / exposed
    151 / 1184 (12.75%)
    68 / 593 (11.47%)
    147 / 592 (24.83%)
    137 / 593 (23.10%)
    88 / 622 (14.15%)
    47 / 312 (15.06%)
    46 / 311 (14.79%)
         occurrences all number
    320
    112
    324
    261
    191
    81
    76
    Influenza like illness
         subjects affected / exposed
    97 / 1184 (8.19%)
    215 / 593 (36.26%)
    87 / 592 (14.70%)
    140 / 593 (23.61%)
    63 / 622 (10.13%)
    27 / 312 (8.65%)
    75 / 311 (24.12%)
         occurrences all number
    125
    363
    119
    210
    84
    36
    137
    Pain
         subjects affected / exposed
    363 / 1184 (30.66%)
    240 / 593 (40.47%)
    189 / 592 (31.93%)
    234 / 593 (39.46%)
    187 / 622 (30.06%)
    90 / 312 (28.85%)
    94 / 311 (30.23%)
         occurrences all number
    720
    485
    385
    501
    364
    162
    180
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    39 / 1184 (3.29%)
    21 / 593 (3.54%)
    58 / 592 (9.80%)
    42 / 593 (7.08%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences all number
    47
    24
    69
    53
    0
    0
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    586 / 1184 (49.49%)
    296 / 593 (49.92%)
    277 / 592 (46.79%)
    281 / 593 (47.39%)
    308 / 622 (49.52%)
    127 / 312 (40.71%)
    135 / 311 (43.41%)
         occurrences all number
    3230
    1587
    1545
    1628
    1851
    740
    820
    Gynaecomastia
         subjects affected / exposed
    84 / 1184 (7.09%)
    38 / 593 (6.41%)
    29 / 592 (4.90%)
    37 / 593 (6.24%)
    47 / 622 (7.56%)
    19 / 312 (6.09%)
    17 / 311 (5.47%)
         occurrences all number
    145
    57
    41
    58
    74
    41
    32
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    129 / 1184 (10.90%)
    56 / 593 (9.44%)
    95 / 592 (16.05%)
    79 / 593 (13.32%)
    59 / 622 (9.49%)
    19 / 312 (6.09%)
    29 / 311 (9.32%)
         occurrences all number
    229
    73
    152
    136
    103
    31
    36
    Dyspnoea
         subjects affected / exposed
    171 / 1184 (14.44%)
    82 / 593 (13.83%)
    122 / 592 (20.61%)
    117 / 593 (19.73%)
    82 / 622 (13.18%)
    45 / 312 (14.42%)
    38 / 311 (12.22%)
         occurrences all number
    362
    154
    256
    253
    169
    99
    72
    Rhinitis
         subjects affected / exposed
    62 / 1184 (5.24%)
    32 / 593 (5.40%)
    41 / 592 (6.93%)
    39 / 593 (6.58%)
    38 / 622 (6.11%)
    17 / 312 (5.45%)
    21 / 311 (6.75%)
         occurrences all number
    102
    55
    71
    61
    65
    24
    39
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    291 / 1184 (24.58%)
    152 / 593 (25.63%)
    189 / 592 (31.93%)
    170 / 593 (28.67%)
    154 / 622 (24.76%)
    69 / 312 (22.12%)
    79 / 311 (25.40%)
         occurrences all number
    784
    362
    457
    416
    389
    142
    198
    Investigations
    Neutrophil count
         subjects affected / exposed
    46 / 1184 (3.89%)
    25 / 593 (4.22%)
    115 / 592 (19.43%)
    111 / 593 (18.72%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences all number
    82
    37
    161
    148
    0
    0
    0
    Alanine aminotransferase
         subjects affected / exposed
    110 / 1184 (9.29%)
    55 / 593 (9.27%)
    69 / 592 (11.66%)
    63 / 593 (10.62%)
    53 / 622 (8.52%)
    29 / 312 (9.29%)
    26 / 311 (8.36%)
         occurrences all number
    218
    102
    139
    140
    116
    73
    52
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    141 / 1184 (11.91%)
    75 / 593 (12.65%)
    88 / 592 (14.86%)
    93 / 593 (15.68%)
    90 / 622 (14.47%)
    40 / 312 (12.82%)
    37 / 311 (11.90%)
         occurrences all number
    252
    152
    141
    158
    169
    69
    65
    Headache
         subjects affected / exposed
    161 / 1184 (13.60%)
    86 / 593 (14.50%)
    95 / 592 (16.05%)
    98 / 593 (16.53%)
    100 / 622 (16.08%)
    35 / 312 (11.22%)
    38 / 311 (12.22%)
         occurrences all number
    334
    153
    190
    172
    202
    63
    80
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    322 / 1184 (27.20%)
    212 / 593 (35.75%)
    228 / 592 (38.51%)
    252 / 593 (42.50%)
    172 / 622 (27.65%)
    78 / 312 (25.00%)
    108 / 311 (34.73%)
         occurrences all number
    931
    653
    691
    902
    495
    255
    370
    Eye disorders
    Vision blurred
         subjects affected / exposed
    54 / 1184 (4.56%)
    27 / 593 (4.55%)
    44 / 592 (7.43%)
    61 / 593 (10.29%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences all number
    85
    54
    73
    105
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    160 / 1184 (13.51%)
    76 / 593 (12.82%)
    114 / 592 (19.26%)
    127 / 593 (21.42%)
    89 / 622 (14.31%)
    60 / 312 (19.23%)
    54 / 311 (17.36%)
         occurrences all number
    298
    131
    200
    203
    161
    95
    106
    Constipation
         subjects affected / exposed
    218 / 1184 (18.41%)
    147 / 593 (24.79%)
    207 / 592 (34.97%)
    212 / 593 (35.75%)
    125 / 622 (20.10%)
    46 / 312 (14.74%)
    70 / 311 (22.51%)
         occurrences all number
    440
    278
    389
    436
    268
    81
    147
    Diarrhoea
         subjects affected / exposed
    251 / 1184 (21.20%)
    139 / 593 (23.44%)
    247 / 592 (41.72%)
    233 / 593 (39.29%)
    134 / 622 (21.54%)
    85 / 312 (27.24%)
    77 / 311 (24.76%)
         occurrences all number
    495
    250
    499
    451
    274
    143
    133
    Dyspepsia
         subjects affected / exposed
    155 / 1184 (13.09%)
    76 / 593 (12.82%)
    137 / 592 (23.14%)
    125 / 593 (21.08%)
    97 / 622 (15.59%)
    67 / 312 (21.47%)
    57 / 311 (18.33%)
         occurrences all number
    314
    123
    245
    208
    221
    110
    102
    Flatulence
         subjects affected / exposed
    167 / 1184 (14.10%)
    79 / 593 (13.32%)
    88 / 592 (14.86%)
    78 / 593 (13.15%)
    105 / 622 (16.88%)
    48 / 312 (15.38%)
    43 / 311 (13.83%)
         occurrences all number
    395
    160
    158
    132
    252
    89
    105
    Haemorrhage
         subjects affected / exposed
    90 / 1184 (7.60%)
    36 / 593 (6.07%)
    44 / 592 (7.43%)
    46 / 593 (7.76%)
    48 / 622 (7.72%)
    15 / 312 (4.81%)
    20 / 311 (6.43%)
         occurrences all number
    148
    70
    71
    74
    81
    28
    35
    Nausea
         subjects affected / exposed
    128 / 1184 (10.81%)
    77 / 593 (12.98%)
    151 / 592 (25.51%)
    152 / 593 (25.63%)
    80 / 622 (12.86%)
    43 / 312 (13.78%)
    37 / 311 (11.90%)
         occurrences all number
    210
    131
    226
    265
    126
    57
    59
    Vomiting
         subjects affected / exposed
    61 / 1184 (5.15%)
    30 / 593 (5.06%)
    57 / 592 (9.63%)
    65 / 593 (10.96%)
    41 / 622 (6.59%)
    23 / 312 (7.37%)
    24 / 311 (7.72%)
         occurrences all number
    81
    39
    73
    88
    52
    25
    35
    Stomatitis
         subjects affected / exposed
    36 / 1184 (3.04%)
    25 / 593 (4.22%)
    153 / 592 (25.84%)
    149 / 593 (25.13%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences all number
    57
    31
    210
    216
    0
    0
    0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    65 / 1184 (5.49%)
    35 / 593 (5.90%)
    37 / 592 (6.25%)
    44 / 593 (7.42%)
    27 / 622 (4.34%)
    27 / 312 (8.65%)
    27 / 311 (8.68%)
         occurrences all number
    105
    69
    71
    78
    49
    52
    44
    Skin and subcutaneous tissue disorders
    Nail discolouration
         subjects affected / exposed
    61 / 1184 (5.15%)
    37 / 593 (6.24%)
    258 / 592 (43.58%)
    194 / 593 (32.72%)
    35 / 622 (5.63%)
    16 / 312 (5.13%)
    23 / 311 (7.40%)
         occurrences all number
    109
    51
    583
    406
    53
    21
    47
    Rash
         subjects affected / exposed
    117 / 1184 (9.88%)
    67 / 593 (11.30%)
    73 / 592 (12.33%)
    70 / 593 (11.80%)
    70 / 622 (11.25%)
    48 / 312 (15.38%)
    41 / 311 (13.18%)
         occurrences all number
    199
    91
    104
    116
    126
    77
    67
    Alopecia
         subjects affected / exposed
    7 / 1184 (0.59%)
    2 / 593 (0.34%)
    80 / 592 (13.51%)
    69 / 593 (11.64%)
    0 / 622 (0.00%)
    0 / 312 (0.00%)
    0 / 311 (0.00%)
         occurrences all number
    7
    3
    136
    118
    0
    0
    0
    Renal and urinary disorders
    Urine output
         subjects affected / exposed
    605 / 1184 (51.10%)
    308 / 593 (51.94%)
    307 / 592 (51.86%)
    279 / 593 (47.05%)
    310 / 622 (49.84%)
    146 / 312 (46.79%)
    138 / 311 (44.37%)
         occurrences all number
    2125
    957
    969
    934
    1130
    514
    438
    Acute kidney injury
         subjects affected / exposed
    92 / 1184 (7.77%)
    71 / 593 (11.97%)
    49 / 592 (8.28%)
    75 / 593 (12.65%)
    51 / 622 (8.20%)
    25 / 312 (8.01%)
    57 / 311 (18.33%)
         occurrences all number
    183
    232
    95
    201
    101
    47
    171
    Haematuria
         subjects affected / exposed
    0 / 1184 (0.00%)
    0 / 593 (0.00%)
    0 / 592 (0.00%)
    0 / 593 (0.00%)
    40 / 622 (6.43%)
    21 / 312 (6.73%)
    14 / 311 (4.50%)
         occurrences all number
    0
    0
    0
    0
    60
    30
    16
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    144 / 1184 (12.16%)
    69 / 593 (11.64%)
    64 / 592 (10.81%)
    64 / 593 (10.79%)
    87 / 622 (13.99%)
    28 / 312 (8.97%)
    35 / 311 (11.25%)
         occurrences all number
    246
    109
    107
    97
    154
    45
    71
    Myalgia
         subjects affected / exposed
    184 / 1184 (15.54%)
    109 / 593 (18.38%)
    133 / 592 (22.47%)
    141 / 593 (23.78%)
    101 / 622 (16.24%)
    34 / 312 (10.90%)
    53 / 311 (17.04%)
         occurrences all number
    316
    186
    226
    265
    158
    60
    99
    Arthralgia
         subjects affected / exposed
    303 / 1184 (25.59%)
    189 / 593 (31.87%)
    202 / 592 (34.12%)
    214 / 593 (36.09%)
    182 / 622 (29.26%)
    87 / 312 (27.88%)
    94 / 311 (30.23%)
         occurrences all number
    787
    426
    513
    525
    495
    220
    270
    Bone pain
         subjects affected / exposed
    436 / 1184 (36.82%)
    235 / 593 (39.63%)
    191 / 592 (32.26%)
    232 / 593 (39.12%)
    249 / 622 (40.03%)
    114 / 312 (36.54%)
    120 / 311 (38.59%)
         occurrences all number
    920
    531
    442
    517
    564
    240
    301
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    94 / 1184 (7.94%)
    57 / 593 (9.61%)
    81 / 592 (13.68%)
    83 / 593 (14.00%)
    52 / 622 (8.36%)
    27 / 312 (8.65%)
    34 / 311 (10.93%)
         occurrences all number
    119
    73
    108
    104
    64
    30
    39
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    39 / 1184 (3.29%)
    64 / 593 (10.79%)
    32 / 592 (5.41%)
    57 / 593 (9.61%)
    26 / 622 (4.18%)
    16 / 312 (5.13%)
    25 / 311 (8.04%)
         occurrences all number
    55
    98
    42
    91
    42
    23
    34
    Anorexia nervosa
         subjects affected / exposed
    91 / 1184 (7.69%)
    49 / 593 (8.26%)
    73 / 592 (12.33%)
    74 / 593 (12.48%)
    56 / 622 (9.00%)
    32 / 312 (10.26%)
    35 / 311 (11.25%)
         occurrences all number
    120
    78
    85
    118
    79
    40
    47

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

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