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    Clinical Trial Results:
    A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride in combination with exemestane and everolimus versus placebo in combination with exemestane and everolimus when administered to metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases.

    Summary
    EudraCT number
    2014-002114-23
    Trial protocol
    IT   GB   ES   AT   CZ   NL   DE   BE   FR  
    Global end of trial date
    28 Oct 2022

    Results information
    Results version number
    v1
    This version publication date
    08 Nov 2023
    First version publication date
    08 Nov 2023
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY88-8223/17096
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02258451
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to assess efficacy and safety of radium 223 dichloride in combination with exemestane and everolimus in subjects with human epidermal growth factor receptor 2 (HER2) negative, hormone receptor positive breast cancer with bone metastases.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Regulatory reason
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Singapore: 17
    Country: Number of subjects enrolled
    Israel: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    283
    EEA total number of subjects
    152
    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)
    185
    From 65 to 84 years
    95
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted with first subject first visit on 04-JUN-2015 and last subject last visit on 28-OCT-2022.

    Pre-assignment
    Screening details
    Overall, 389 subjects were screened and 283 were assigned to treatment. Of these, 142 subjects in the radium 223 dichloride arm and 141 subjects in the placebo arm.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Radium-223 + EXE/EVE
    Arm description
    Subjects randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.
    Arm type
    Experimental

    Investigational medicinal product name
    Radium-223 dichloride (Xofigo, BAY88-8223)
    Investigational medicinal product code
    BAY88-8223
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55kBq/kg after implementation of NIST update).

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 25 mg tablet once daily after a meal.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended dose of everolimus administered in the study was 10 mg once daily with or without food. Starting dose, dose modifications, and administration of exemestane and everolimus were in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

    Arm title
    Placebo + EXE/EVE
    Arm description
    Subjects randomized to treatment with placebo, also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Up to 6 cycles of saline injection.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 25 mg tablet once daily after a meal.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended dose of everolimus administered in the study was 10 mg once daily with or without food. Starting dose, dose modifications, and administration of exemestane and everolimus were in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

    Number of subjects in period 1
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Started
    142
    141
    Completed
    0
    0
    Not completed
    142
    141
         Stop all drugs due to AE not associated with CP
    8
    1
         Stop all drugs due to AE associated with CP
    8
    6
         Stop all drugs due to physician decision
    -
    2
         Stop all drugs due to other reason
    1
    1
         Stop all drugs due to end point reached
    1
    1
         Stop all drugs due to clinical progression (CP)
    7
    7
         Stop all drugs due to withdrawal by subjects
    21
    13
         Never treated
    2
    3
         Stop all drugs due to study terminated by sponsor
    -
    3
         Stop all drugs due to death
    4
    3
         Stop all drugs due to radiological progression
    90
    101

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radium-223 + EXE/EVE
    Reporting group description
    Subjects randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

    Reporting group title
    Placebo + EXE/EVE
    Reporting group description
    Subjects randomized to treatment with placebo, also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

    Reporting group values
    Radium-223 + EXE/EVE Placebo + EXE/EVE Total
    Number of subjects
    142 141 283
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.95 ( 10.40 ) 59.08 ( 11.64 ) -
    Gender categorical
    Units: Subjects
        Female
    142 141 283

    End points

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    End points reporting groups
    Reporting group title
    Radium-223 + EXE/EVE
    Reporting group description
    Subjects randomized to treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology (NIST) update) also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

    Reporting group title
    Placebo + EXE/EVE
    Reporting group description
    Subjects randomized to treatment with placebo, also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

    Subject analysis set title
    Intent-to-treat analysis set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    included all randomized subjects.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    included all randomized subjects who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus). Subjects were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.

    Subject analysis set title
    Radium-223 + EXE/EVE
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received treatment with radium-223 dichloride, 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update) also received exemestane (EXE), 25 mg tablet once daily (after a meal), and everolimus (EVE), 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

    Subject analysis set title
    Placebo + EXE/EVE
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects did not receive any radium-223 dichloride, but received treatment with any study treatment (placebo, exemestane [25 mg tablet once daily (after a meal)], and everolimus [10 mg once daily (with or without food)]), and supportive care as per the local or institutional standard of practice.

    Primary: Symptomatic skeletal event-free survival (SSE-FS)

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    End point title
    Symptomatic skeletal event-free survival (SSE-FS)
    End point description
    Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.
    End point type
    Primary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    142 [1]
    141 [2]
    Units: Months
        median (confidence interval 95%)
    21.1 (17.1 to 23.6)
    19.9 (16.2 to 24.2)
    Notes
    [1] - Intent-to-treat analysis set
    [2] - Intent-to-treat analysis set
    Statistical analysis title
    Hazard ratio (Radium-223 / Placebo)
    Statistical analysis description
    The 1-sided null hypothesis that treatment with radium-223 dichloride does not result in superior SSE-FS to treatment with placebo in subject population was tested against the 1-sided alternative hypothesis that the treatment with radium-223 dichloride results in superior SSE-FS time to treatment the placebo. H0: SSE-FS Radium-223+Exemestane/Everolimus <= SSE-FS Placebo+Exemestane/Everolimus, versus HA: SSE-FS Radium-223+Exemestane/Everolimus > SSE-FS Placebo+Exemestane/Everolimus
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4843 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.891
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.102
    Notes
    [3] - 1-sided SSE-FS hypotheses were tested using a log-rank test with a 2-sided alpha of 0.2, stratified by the randomization stratification factors

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    The time from the date of randomization to the date of death due to any cause. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.
    End point type
    Secondary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    142 [4]
    141 [5]
    Units: Months
        median (confidence interval 95%)
    25.0 (23.0 to 31.4)
    26.4 (21.7 to 28.9)
    Notes
    [4] - Intent-to-treat analysis set
    [5] - Intent-to-treat analysis set
    Statistical analysis title
    Hazard ratio (Radium-223 / Placebo)
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8438 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.968
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.697
         upper limit
    1.343
    Notes
    [6] - P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.

    Secondary: Time to opiate use for cancer pain

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    End point title
    Time to opiate use for cancer pain
    End point description
    Interval from the date of randomization to the date of opiate use. 95% Confidence Interval = 99999, value cannot be estimated due to censored data. Insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [7]
    139 [8]
    Units: Months
        median (confidence interval 95%)
    21.4 (13.2 to 99999)
    18.4 (8.3 to 99999)
    Notes
    [7] - Safety analysis set 99999 = Insufficient number of subjects with events.
    [8] - Safety analysis set 99999 = Insufficient number of subjects with events.
    Statistical analysis title
    Hazard ratio (Radium-223 / Placebo)
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8811 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.962
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.577
         upper limit
    1.604
    Notes
    [9] - P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.

    Secondary: Time to pain progression

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    End point title
    Time to pain progression
    End point description
    Time from randomization to the first date a subject experienced pain progression based on worst pain score (WPS). Pain progression was defined as an increase of 2 or more points in the Brief Pain Inventory-Short Form (BPI-SF) “Worst pain in 24 hours” score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in subjects not taking opioids at baseline, the initiation of a strong opioid in subjects taking a weak opioid at baseline, or the initiation of an additional strong opioid in subjects taking a strong opioid at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [10]
    139 [11]
    Units: Months
        median (confidence interval 95%)
    7.6 (6.2 to 13.2)
    5.7 (4.9 to 8.5)
    Notes
    [10] - Safety analysis set
    [11] - Safety analysis set
    Statistical analysis title
    Hazard ratio (Radium-223 / Placebo)
    Statistical analysis description
    Subjects with baseline WPS > 8 were included in the analysis population but censored at Day 1.
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6537 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.928
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.667
         upper limit
    1.289
    Notes
    [12] - P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.

    Secondary: Time to cytotoxic chemotherapy

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    End point title
    Time to cytotoxic chemotherapy
    End point description
    Time from the date of randomization to the date of the first cytotoxic chemotherapy
    End point type
    Secondary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    142 [13]
    141 [14]
    Units: Months
        median (confidence interval 95%)
    13.7 (9.9 to 15.8)
    11.6 (9.0 to 16.4)
    Notes
    [13] - Intent-to-treat analysis set
    [14] - Intent-to-treat analysis set
    Statistical analysis title
    Hazard ratio (Radium-223 / Placebo)
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4496 [15]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.884
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.641
         upper limit
    1.219
    Notes
    [15] - P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.

    Secondary: Radiological progression-free survival (rPFS)

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    End point title
    Radiological progression-free survival (rPFS)
    End point description
    Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression). Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.
    End point type
    Secondary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    142 [16]
    141 [17]
    Units: Months
        median (confidence interval 95%)
    7.9 (6.2 to 9.7)
    6.7 (5.4 to 8.1)
    Notes
    [16] - Intent-to-treat analysis set
    [17] - Intent-to-treat analysis set
    Statistical analysis title
    Hazard ratio (Radium-223 / Placebo)
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3467 [18]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.874
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.157
    Notes
    [18] - P-value was calculated using a 2-sided log-rank test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.

    Secondary: Percentage of subjects with pain improvement

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    End point title
    Percentage of subjects with pain improvement
    End point description
    In the percentage of subjects with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in subjects not taking opioids at baseline, the initiation of a strong opioid in subjects taking a weak opioid at baseline, or the initiation of an additional strong opioid in subjects taking a strong opioid at baseline. Safety analysis set with baseline WPS >= 2: all randomized subjects who received at least one dose of any study medication (radium 223 dichloride or placebo exemestane, or everolimus), and who in addition had baseline BPI-SF WPS >= 2. Subjects were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.
    End point type
    Secondary
    End point timeframe
    Up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    91 [19]
    96 [20]
    Units: percentage of subjects
        number (confidence interval 95%)
    38.5 (28.4 to 49.2)
    34.4 (25.0 to 44.8)
    Notes
    [19] - Safety analysis set
    [20] - Safety analysis set
    Statistical analysis title
    Difference (Radium-223 - Placebo)
    Comparison groups
    Radium-223 + EXE/EVE v Placebo + EXE/EVE
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.556 [21]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    4.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.2
         upper limit
    18.4
    Notes
    [21] - P-value was calculated using a 2-sided Cochran-Mantel-Haenszel test stratified by the same stratification factors as randomization. No alpha adjustment for multiplicity was applied.

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs)

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    End point title
    Number of subjects with treatment-emergent adverse events (TEAEs)
    End point description
    An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.
    End point type
    Secondary
    End point timeframe
    From first dosing up to 30 days after the last administration of study treatments, up to 89 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [22]
    139 [23]
    Units: Subjects
        Any TEAE
    139
    136
        Serious TEAE
    57
    55
        Radium-223/Placebo-related TEAEs
    73
    50
        Exemestane-related TEAEs
    75
    64
        Everolimus-related TEAEs
    130
    125
    Notes
    [22] - Safety analysis set
    [23] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Number of subjects with post-treatment chemotherapy related adverse events

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    End point title
    Number of subjects with post-treatment chemotherapy related adverse events
    End point description
    According to protocol amendment 10, all subjects who completed the EOT visit will be transferred to a separate extended safety follow-up study for their remaining follow-up. Thus, no further post-treatment data were collected after protocol amendment 10.
    End point type
    Secondary
    End point timeframe
    From post-treatment till end of study, up to 89 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [24]
    139 [25]
    Units: Subjects
        All system organ classes_Any_Grade 3
    1
    0
        All system organ classes_Any_Grade 4
    1
    0
        Blood and lymphatic system disorders_Any_Grade 3
    1
    0
        Febrile neutropenia_Grade 3
    1
    0
        Investigations_Any_Grade 4
    1
    0
        Investigations_Neutrophil count decreased_Grade 4
    1
    0
    Notes
    [24] - Safety analysis set
    [25] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Number of subjects with hematological toxicities: Worst Grade under Treatment

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    End point title
    Number of subjects with hematological toxicities: Worst Grade under Treatment
    End point description
    Safety analysis set with at least one hematology lab assessment: all randomized subjects who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. Subjects were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.
    End point type
    Secondary
    End point timeframe
    From first dosing up to 30 days after the last administration of study treatments, up to 89 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [26]
    137 [27]
    Units: Subjects
        Anemia Grade 1
    61
    57
        Anemia Grade 2
    43
    55
        Anemia Grade 3
    21
    11
        Anemia Grade 4
    0
    0
        Anemia Normal
    14
    14
        Leukocytosis Grade 1
    0
    0
        Leukocytosis Grade 2
    0
    0
        Leukocytosis Grade 3
    0
    0
        Leukocytosis Grade 4
    0
    0
        Leukocytosis Normal
    139
    137
        Hemoglobin increased Grade 1
    0
    0
        Hemoglobin increased Grade 2
    1
    0
        Hemoglobin increased Grade 3
    0
    0
        Hemoglobin increased Grade 4
    0
    0
        Hemoglobin increased Normal
    138
    137
        Lymphocyte count decreased Grade 1
    20
    33
        Lymphocyte count decreased Grade 2
    63
    45
        Lymphocyte count decreased Grade 3
    43
    24
        Lymphocyte count decreased Grade 4
    2
    0
        Lymphocyte count decreased Normal
    11
    35
        Lymphocyte count increased Grade 1
    0
    0
        Lymphocyte count increased Grade 2
    2
    2
        Lymphocyte count increased Grade 3
    0
    0
        Lymphocyte count increased Grade 4
    0
    0
        Lymphocyte count increased Normal
    137
    135
        Neutrophil count decreased Grade 1
    23
    30
        Neutrophil count decreased Grade 2
    48
    28
        Neutrophil count decreased Grade 3
    19
    0
        Neutrophil count decreased Grade 4
    0
    2
        Neutrophil count decreased Normal
    49
    77
        Platelet count decreased Grade 1
    60
    60
        Platelet count decreased Grade 2
    7
    3
        Platelet count decreased Grade 3
    7
    0
        Platelet count decreased Grade 4
    1
    0
        Platelet count decreased Normal
    64
    74
        White blood cell decreased Grade 1
    37
    48
        White blood cell decreased Grade 2
    59
    37
        White blood cell decreased Grade 3
    17
    3
        White blood cell decreased Grade 4
    1
    1
        White blood cell decreased Normal
    25
    48
    Notes
    [26] - Safety analysis set
    [27] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Number of subjects with new primary malignancies

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    End point title
    Number of subjects with new primary malignancies
    End point description
    End point type
    Secondary
    End point timeframe
    From first dosing till end of study, up to 89 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [28]
    139 [29]
    Units: Subjects
    1
    0
    Notes
    [28] - Safety analysis set
    [29] - Safety analysis set
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with treatment-emergent adverse events (TEAEs) (From first dosing till primary analysis)

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    End point title
    Number of subjects with treatment-emergent adverse events (TEAEs) (From first dosing till primary analysis)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dosing till primary analysis cutoff date, up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [30]
    139 [31]
    Units: Subjects
        Any TEAE
    139
    136
        Serious TEAE
    57
    53
        Radium-223/Placebo-related TEAEs
    73
    50
        Exemestane-related TEAEs
    75
    64
        Everolimus-related TEAEs
    130
    125
    Notes
    [30] - Safety analysis set
    [31] - Safety analysis set
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with post-treatment chemotherapy related adverse events (From first dosing till primary analysis)

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    End point title
    Number of subjects with post-treatment chemotherapy related adverse events (From first dosing till primary analysis)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From post-treatment till primary analysis cutoff date, up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [32]
    139 [33]
    Units: Subjects
        All system organ classes_Any_Grade 3
    1
    0
        All system organ classes_Any_Grade 4
    1
    0
        Blood and lymphatic system disorders_Any_Grade 3
    1
    0
        Febrile neutropenia_Grade 3
    1
    0
        Investigations_Any_Grade 4
    1
    0
        Investigations_Neutrophil count decreased_Grade 4
    1
    0
    Notes
    [32] - Safety analysis set
    [33] - Safety analysis set
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with hematological toxicities: Worst Grade under Treatment (From first dosing till primary analysis)

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    End point title
    Number of subjects with hematological toxicities: Worst Grade under Treatment (From first dosing till primary analysis)
    End point description
    Safety analysis set with at least one hematology lab assessment: all randomized subjects who received at least one dose of any study medication (radium 223 dichloride or placebo, exemestane, and everolimus), and who in addition had at least one hematology lab assessment. subjects were assigned to the Radium-223 dichloride arm if they received any dose of Radium-223 dichloride, otherwise to the placebo arm.
    End point type
    Other pre-specified
    End point timeframe
    From first dosing till primary analysis cutoff date, up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [34]
    137 [35]
    Units: Subjects
        Anemia Grade 1
    61
    57
        Anemia Grade 2
    43
    55
        Anemia Grade 3
    21
    11
        Anemia Grade 4
    0
    0
        Anemia Normal
    14
    14
        Leukocytosis Grade 1
    0
    0
        Leukocytosis Grade 2
    0
    0
        Leukocytosis Grade 3
    0
    0
        Leukocytosis Grade 4
    0
    0
        Leukocytosis Normal
    139
    137
        Hemoglobin increased Grade 1
    0
    0
        Hemoglobin increased Grade 2
    1
    0
        Hemoglobin increased Grade 3
    0
    0
        Hemoglobin increased Grade 4
    0
    0
        Hemoglobin increased Normal
    138
    137
        Lymphocyte count decreased Grade 1
    20
    33
        Lymphocyte count decreased Grade 2
    63
    45
        Lymphocyte count decreased Grade 3
    43
    24
        Lymphocyte count decreased Grade 4
    2
    0
        Lymphocyte count decreased Normal
    11
    35
        Lymphocyte count increased Grade 1
    0
    0
        Lymphocyte count increased Grade 2
    2
    2
        Lymphocyte count increased Grade 3
    0
    0
        Lymphocyte count increased Grade 4
    0
    0
        Lymphocyte count increased Normal
    137
    135
        Neutrophil count decreased Grade 1
    24
    29
        Neutrophil count decreased Grade 2
    47
    28
        Neutrophil count decreased Grade 3
    19
    0
        Neutrophil count decreased Grade 4
    0
    2
        Neutrophil count decreased Normal
    49
    78
        Platelet count decreased Grade 1
    60
    61
        Platelet count decreased Grade 2
    7
    2
        Platelet count decreased Grade 3
    7
    0
        Platelet count decreased Grade 4
    1
    0
        Platelet count decreased Normal
    64
    74
        White blood cell decreased Grade 1
    37
    47
        White blood cell decreased Grade 2
    59
    36
        White blood cell decreased Grade 3
    17
    3
        White blood cell decreased Grade 4
    1
    1
        White blood cell decreased Normal
    25
    50
    Notes
    [34] - Safety analysis set
    [35] - Safety analysis set
    No statistical analyses for this end point

    Other pre-specified: Number of subjects with new primary malignancies during study treatment till primary analysis

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    End point title
    Number of subjects with new primary malignancies during study treatment till primary analysis
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From first dosing till primary analysis cutoff date, up to 55 months
    End point values
    Radium-223 + EXE/EVE Placebo + EXE/EVE
    Number of subjects analysed
    139 [36]
    139 [37]
    Units: Subjects
    1
    0
    Notes
    [36] - Safety analysis set
    [37] - Safety analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For AE: After providing written informed consent for participation in the study till end of study, up to 90 months.
    Adverse event reporting additional description
    Time Frame for death: Considers all deaths that occurred at any time during the study of 17096 before the last contact, up to 90 months.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo + EXE/EVE
    Reporting group description
    Subjects were randomized to treatment with placebo, also with exemestane and everolimus and supportive care as per the local or institutional standard of practice

    Reporting group title
    Radium-223 + EXE/EVE
    Reporting group description
    Subjects were randomized to treatment with radium-223 dichloride, also with exemestane and everolimus and supportive care as per the local or institutional standard of practice

    Serious adverse events
    Placebo + EXE/EVE Radium-223 + EXE/EVE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 139 (40.29%)
    61 / 139 (43.88%)
         number of deaths (all causes)
    67
    66
         number of deaths resulting from adverse events
    8
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Appendix cancer metastatic
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Metastases to ovary
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 139 (2.16%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Performance status decreased
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    3 / 139 (2.16%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injection site extravasation
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    2 / 139 (1.44%)
    7 / 139 (5.04%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 139 (3.60%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy lung
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bell's palsy
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medullary compression syndrome
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysmetria
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 139 (3.60%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    8 / 12
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 139 (0.00%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (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 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (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
    Urticaria
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 139 (2.16%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    4 / 139 (2.88%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 139 (2.88%)
    5 / 139 (3.60%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + EXE/EVE Radium-223 + EXE/EVE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    135 / 139 (97.12%)
    139 / 139 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 139 (5.04%)
    13 / 139 (9.35%)
         occurrences all number
    11
    22
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 139 (18.71%)
    29 / 139 (20.86%)
         occurrences all number
    52
    48
    Fatigue
         subjects affected / exposed
    41 / 139 (29.50%)
    38 / 139 (27.34%)
         occurrences all number
    60
    66
    Oedema peripheral
         subjects affected / exposed
    25 / 139 (17.99%)
    26 / 139 (18.71%)
         occurrences all number
    34
    37
    Pyrexia
         subjects affected / exposed
    13 / 139 (9.35%)
    20 / 139 (14.39%)
         occurrences all number
    16
    27
    Peripheral swelling
         subjects affected / exposed
    10 / 139 (7.19%)
    8 / 139 (5.76%)
         occurrences all number
    17
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 139 (18.71%)
    25 / 139 (17.99%)
         occurrences all number
    40
    37
    Dyspnoea
         subjects affected / exposed
    17 / 139 (12.23%)
    16 / 139 (11.51%)
         occurrences all number
    25
    20
    Epistaxis
         subjects affected / exposed
    14 / 139 (10.07%)
    9 / 139 (6.47%)
         occurrences all number
    15
    12
    Pneumonitis
         subjects affected / exposed
    16 / 139 (11.51%)
    16 / 139 (11.51%)
         occurrences all number
    19
    20
    Oropharyngeal pain
         subjects affected / exposed
    8 / 139 (5.76%)
    7 / 139 (5.04%)
         occurrences all number
    10
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 139 (10.07%)
    15 / 139 (10.79%)
         occurrences all number
    16
    15
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 139 (16.55%)
    21 / 139 (15.11%)
         occurrences all number
    52
    51
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 139 (15.11%)
    19 / 139 (13.67%)
         occurrences all number
    40
    44
    Blood cholesterol increased
         subjects affected / exposed
    10 / 139 (7.19%)
    15 / 139 (10.79%)
         occurrences all number
    22
    22
    Blood creatinine increased
         subjects affected / exposed
    10 / 139 (7.19%)
    11 / 139 (7.91%)
         occurrences all number
    23
    26
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 139 (5.04%)
    8 / 139 (5.76%)
         occurrences all number
    14
    36
    Neutrophil count decreased
         subjects affected / exposed
    6 / 139 (4.32%)
    14 / 139 (10.07%)
         occurrences all number
    11
    43
    Platelet count decreased
         subjects affected / exposed
    12 / 139 (8.63%)
    12 / 139 (8.63%)
         occurrences all number
    28
    42
    Weight decreased
         subjects affected / exposed
    22 / 139 (15.83%)
    28 / 139 (20.14%)
         occurrences all number
    31
    37
    White blood cell count decreased
         subjects affected / exposed
    13 / 139 (9.35%)
    13 / 139 (9.35%)
         occurrences all number
    31
    43
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 139 (6.47%)
    9 / 139 (6.47%)
         occurrences all number
    12
    11
    Dysgeusia
         subjects affected / exposed
    13 / 139 (9.35%)
    17 / 139 (12.23%)
         occurrences all number
    14
    26
    Headache
         subjects affected / exposed
    30 / 139 (21.58%)
    25 / 139 (17.99%)
         occurrences all number
    42
    35
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    40 / 139 (28.78%)
    55 / 139 (39.57%)
         occurrences all number
    146
    191
    Neutropenia
         subjects affected / exposed
    11 / 139 (7.91%)
    29 / 139 (20.86%)
         occurrences all number
    11
    73
    Thrombocytopenia
         subjects affected / exposed
    9 / 139 (6.47%)
    21 / 139 (15.11%)
         occurrences all number
    19
    58
    Leukopenia
         subjects affected / exposed
    2 / 139 (1.44%)
    12 / 139 (8.63%)
         occurrences all number
    3
    49
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 139 (0.72%)
    8 / 139 (5.76%)
         occurrences all number
    1
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 139 (7.91%)
    7 / 139 (5.04%)
         occurrences all number
    13
    7
    Abdominal pain upper
         subjects affected / exposed
    7 / 139 (5.04%)
    15 / 139 (10.79%)
         occurrences all number
    8
    18
    Constipation
         subjects affected / exposed
    20 / 139 (14.39%)
    6 / 139 (4.32%)
         occurrences all number
    23
    7
    Diarrhoea
         subjects affected / exposed
    31 / 139 (22.30%)
    42 / 139 (30.22%)
         occurrences all number
    54
    66
    Dry mouth
         subjects affected / exposed
    9 / 139 (6.47%)
    10 / 139 (7.19%)
         occurrences all number
    9
    13
    Dyspepsia
         subjects affected / exposed
    7 / 139 (5.04%)
    7 / 139 (5.04%)
         occurrences all number
    8
    8
    Mouth ulceration
         subjects affected / exposed
    10 / 139 (7.19%)
    3 / 139 (2.16%)
         occurrences all number
    19
    3
    Nausea
         subjects affected / exposed
    30 / 139 (21.58%)
    41 / 139 (29.50%)
         occurrences all number
    42
    55
    Stomatitis
         subjects affected / exposed
    69 / 139 (49.64%)
    66 / 139 (47.48%)
         occurrences all number
    172
    144
    Vomiting
         subjects affected / exposed
    22 / 139 (15.83%)
    25 / 139 (17.99%)
         occurrences all number
    31
    32
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    9 / 139 (6.47%)
    7 / 139 (5.04%)
         occurrences all number
    31
    11
    Dry skin
         subjects affected / exposed
    14 / 139 (10.07%)
    8 / 139 (5.76%)
         occurrences all number
    15
    8
    Pruritus
         subjects affected / exposed
    14 / 139 (10.07%)
    17 / 139 (12.23%)
         occurrences all number
    20
    18
    Rash
         subjects affected / exposed
    30 / 139 (21.58%)
    20 / 139 (14.39%)
         occurrences all number
    44
    29
    Rash maculo-papular
         subjects affected / exposed
    7 / 139 (5.04%)
    9 / 139 (6.47%)
         occurrences all number
    14
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 139 (30.22%)
    30 / 139 (21.58%)
         occurrences all number
    81
    51
    Back pain
         subjects affected / exposed
    26 / 139 (18.71%)
    16 / 139 (11.51%)
         occurrences all number
    36
    17
    Bone pain
         subjects affected / exposed
    24 / 139 (17.27%)
    16 / 139 (11.51%)
         occurrences all number
    34
    31
    Musculoskeletal pain
         subjects affected / exposed
    8 / 139 (5.76%)
    4 / 139 (2.88%)
         occurrences all number
    10
    4
    Myalgia
         subjects affected / exposed
    7 / 139 (5.04%)
    9 / 139 (6.47%)
         occurrences all number
    8
    10
    Pain in extremity
         subjects affected / exposed
    25 / 139 (17.99%)
    21 / 139 (15.11%)
         occurrences all number
    37
    28
    Pathological fracture
         subjects affected / exposed
    15 / 139 (10.79%)
    16 / 139 (11.51%)
         occurrences all number
    23
    22
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 139 (8.63%)
    6 / 139 (4.32%)
         occurrences all number
    15
    7
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 139 (1.44%)
    9 / 139 (6.47%)
         occurrences all number
    4
    12
    Spinal pain
         subjects affected / exposed
    9 / 139 (6.47%)
    7 / 139 (5.04%)
         occurrences all number
    13
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    12 / 139 (8.63%)
    12 / 139 (8.63%)
         occurrences all number
    14
    16
    Conjunctivitis
         subjects affected / exposed
    3 / 139 (2.16%)
    8 / 139 (5.76%)
         occurrences all number
    3
    8
    Cystitis
         subjects affected / exposed
    7 / 139 (5.04%)
    4 / 139 (2.88%)
         occurrences all number
    8
    4
    Nasopharyngitis
         subjects affected / exposed
    5 / 139 (3.60%)
    7 / 139 (5.04%)
         occurrences all number
    7
    7
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 139 (14.39%)
    15 / 139 (10.79%)
         occurrences all number
    38
    22
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    6 / 139 (4.32%)
    12 / 139 (8.63%)
         occurrences all number
    9
    28
    Hyperglycaemia
         subjects affected / exposed
    18 / 139 (12.95%)
    17 / 139 (12.23%)
         occurrences all number
    41
    36
    Hypertriglyceridaemia
         subjects affected / exposed
    11 / 139 (7.91%)
    12 / 139 (8.63%)
         occurrences all number
    38
    29
    Hypocalcaemia
         subjects affected / exposed
    8 / 139 (5.76%)
    4 / 139 (2.88%)
         occurrences all number
    14
    4
    Hypokalaemia
         subjects affected / exposed
    14 / 139 (10.07%)
    19 / 139 (13.67%)
         occurrences all number
    27
    29
    Hypophosphataemia
         subjects affected / exposed
    8 / 139 (5.76%)
    11 / 139 (7.91%)
         occurrences all number
    37
    16
    Decreased appetite
         subjects affected / exposed
    35 / 139 (25.18%)
    48 / 139 (34.53%)
         occurrences all number
    43
    68

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2015
    Amendment 1 (global amendment) forming integrated protocol Version 2.0, dated 16 MAR 2015, was an amendment to the original protocol.
    29 Jul 2015
    Amendment 3 (global amendment) forming integrated protocol Version 3.0, dated 29 JUL 2015, is an amendment to the Version 2.0 of the protocol.
    09 Mar 2016
    Amendment 5 (global amendment) forming integrated protocol Version 4.0, dated 09 MAR 2016, is an amendment to the Version 3.0 of the protocol.
    23 May 2017
    Amendment 8 (global amendment) forming integrated protocol Version 5.0, dated 23 MAY 2017, is an amendment to the Version 4.0 of the protocol.
    03 Apr 2018
    Amendment 9 (global amendment) forming integrated protocol Version 6.0, dated 03 APR 2018, is an amendment to the Version 5.0 of the protocol, dated 23 MAY 2017. This was the protocol in effect leading up to the primary analysis discussed in this report.
    04 Dec 2019
    Amendment 10 (global amendment) forming integrated protocol Version 7.0, dated 04 DEC 2019, is an amendment to the Version 6.0 of the protocol, dated 03 APR 2018. This amendment was planned to go into effect once the primary analysis was completed. The data analyzed in clinical study report were collected using the study conduct described in Protocol Amendment 9; however, Protocol Amendment 10 is being included in this summary for completeness as it was approved prior to the database clean date.

    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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