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    Clinical Trial Results:
    REASURE: A phase II randomised trial of biomarkers to assess (dose-) response in patients with metastatic castration resistant prostate cancer treated with radium-223

    Summary
    EudraCT number
    		 2013-004055-20
    Trial protocol
    		 GB  
    Global end of trial date
    06 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Oct 2024
    First version publication date
    17 Oct 2024
    Other versions
    Summary report(s)
    		 Radium-223 in metastatic castration-resistant prostate cancer: whole-body diffusion-weighted magnetic resonance imaging scanning to assess response

    Trial information

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    Trial identification
    Sponsor protocol code
    CCR4108
    Additional study identifiers
    ISRCTN number
    		 ISRCTN17805587
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC Reference Number: 14/LO/1385, ICR-CTSU Protocol Number: ICR-CTSU/2013/10040
    Sponsors
    Sponsor organisation name
    Institute of Cancer research
    Sponsor organisation address
    15 Cotswold Road Sutton, SM2 5NG, London, United Kingdom, SM2 5NG
    Public contact
    Aude Espinasse, The Institute of Cancer Research, reasure-icrctsu@icr.ac.uk
    Scientific contact
    Aude Espinasse, The Institute of Cancer Research, REASURE-icrctsu@icr.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
    Final
    Date of interim/final analysis
    11 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal research question is: can response to radium-223, in patients with CRPC and bone metastases, be measured reliably by functional imaging and/or circulating biomarkers? The primary objective is to evaluate patients' response to treatment using a type of imaging technique called whole body diffusion-weighted MRI (DW-MRI).
    Protection of trial subjects
    For trial entry and optional tissue donation, patients were given a verbal explanation, discussion and written information. The Principal Investigator at each site was responsible for ensuring written informed consent was obtained for each patient. Eligible patients were given as much time as they needed to consider, ask questions and come to a decision about entering the trial, prior to giving consent for entering the trial. The patient information sheet described which parties would have access to their identifiable personal information and patients were asked to give consent to this. The trial was overseen by an Independent Data Monitoring Committee, who reviewed the accumulating trial data and could recommend stopping the trial if there was any cause for concern about patient safety and if this were the case the patient's oncologist would be notified.
    Background therapy
    		 none
    Evidence for comparator
    		 The evaluation of bone predominant disease in patients with metastatic prostate cancer remains challenging. As yet, there is no reliable method to assess and quantify treatment response. Therefore bone metastases are often regarded as non-measurable disease by standard RECIST (v1.1)/PCWG2 criteria [40]. Criteria exist which use radiographic changes to measure response but these are relatively insensitive, taking a number of months for changes to occur [41]. In addition, the criterion of sclerosis of previously osteolytic metastases is not relevant for metastatic disease that is predominantly sclerotic at baseline (as is common in prostate cancer). Given that assessment of response of bone metastases is insensitive and often non-specific, in practice a combination of clinical, biochemical (e.g PSA and ALP) and radiological measures are currently used. However, more accurate means of monitoring response are required to inform early treatment failure or success. Radium-223 was the first bone targeted alpha emitter to be tested in phase III studies. It has demonstrated improved survival for this group of patients with a favourable risk/benefit profile. Radium-223 was approved by the FDA in May 2013 for the treatment of CRPC with bone metastases and was granted marketing authorisation in the EU in November 2013. It is currently authorised to be marketed in more than 43 countries. The present study will explore the role of functional imaging and circulating biomarkers to assess response to radium-223 and potential dose-response relationships.
    Actual start date of recruitment
    27 May 2015
    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: 39
    Worldwide total number of subjects
    39
    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)
    2
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 7/2015 and 6/2017, 39 patients were recruited from 3 UK hospital sites.

    Pre-assignment
    Screening details
    		 Inclusion criteria included histologically/cytologically confirmed adenocarcinoma of the prostate with castrate resistant disease, serum PSA≥2ng/ml, ECOG performance status 0-2, life expectancy > 6 months, and multiple skeletal metastases (≥2 hotspots).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 55 kBq/kg Radium 223
    Arm description
    		 Participants in this arm were allocated to receive 55 kBq/kg of Radium 223. Allocation ratio between the 2 arms was 1:1. Treatment allocation was via minimisation with a random element; balancing factors included patient weight, total ALP and current bisphosphonate use. Dose allocation was not blinded. Patients received treatment with radium-223 at the allocated dose via IV administration every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium 223
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received treatment with radium-223 at 55 kBq/kg via IV administration every 4 weeks for up to 6 cycles.

    Arm title
    		 88 kBq/kg Radium 223
    Arm description
    		 Patients received treatment with radium-223 at the 88 kBq/kg via IV administration every 4 weeks for up to 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium 223
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received treatment with radium-223 at 88 kBq/kg via IV administration every 4 weeks for up to 6 cycles.

    Number of subjects in period 1
    		55 kBq/kg Radium 223 88 kBq/kg Radium 223
    Started
    20
    19
    Completed
    20
    17
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    55 kBq/kg Radium 223
    Reporting group description
    		 Participants in this arm were allocated to receive 55 kBq/kg of Radium 223. Allocation ratio between the 2 arms was 1:1. Treatment allocation was via minimisation with a random element; balancing factors included patient weight, total ALP and current bisphosphonate use. Dose allocation was not blinded. Patients received treatment with radium-223 at the allocated dose via IV administration every 4 weeks for up to 6 cycles.

    Reporting group title
    88 kBq/kg Radium 223
    Reporting group description
    		 Patients received treatment with radium-223 at the 88 kBq/kg via IV administration every 4 weeks for up to 6 cycles.

    Reporting group values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 Total
    Number of subjects
    		 20 19 39
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 1 1 2
        From 65-84 years
    		 19 18 37
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 74.9 (72.6 to 80.1) 74.5 (67.4 to 78.1) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 20 19 39
    Weight at trial entry
    Units: Subjects
        <80kg
    		 9 10 19
        >=80kg
    		 11 9 20
    ALP at trial entry
    Units: Subjects
        <220 U/L
    		 14 16 30
        >=220 U/L
    		 6 3 9
    Prior bisphosphonate use
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 17 17 34
    EOD grade at trial entry
    Units: Subjects
        EOD1
    		 10 8 18
        EOD2
    		 5 9 14
        EOD3
    		 3 1 4
        EOD4
    		 2 1 3
    Lymh node metastases at diagnosis
    Units: Subjects
        Yes
    		 1 7 8
        No
    		 19 12 31
    Gleason score at diagnosis (total)
    Units: Subjects
        Gleason 6
    		 1 2 3
        Gleason 7
    		 7 2 9
        Gleason 8
    		 4 5 9
        Gleason 9
    		 8 9 17
        Missing
    		 0 1 1
    Time since histological confirmation of disease to trial entry
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 2.9 (1.7 to 5.6) 3.9 (3.0 to 7.1) -
    Time since confirmation of bone metastases to trial entry
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 2.0 (1.2 to 3.9) 2.5 (0.5 to 3.9) -
    Time since castration resistance to trial entry
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 0.7 (0.2 to 1.4) 1.4 (0.2 to 3.2) -
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised

    Subject analysis set title
    Imaging study population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Excludes patients with key eligibility deviations

    Subject analysis sets values
    		 ITT Imaging study population
    Number of subjects
    39
    36
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    2
    2
        From 65-84 years
    37
    34
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    74.5 (72.1 to 79.5)
    75.1 (72.8 to 79.5)
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    39
    36
    Weight at trial entry
    Units: Subjects
        <80kg
    19
    18
        >=80kg
    20
    18
    ALP at trial entry
    Units: Subjects
        <220 U/L
    30
    29
        >=220 U/L
    9
    7
    Prior bisphosphonate use
    Units: Subjects
        Yes
    5
    4
        No
    34
    32
    EOD grade at trial entry
    Units: Subjects
        EOD1
    18
    17
        EOD2
    14
    13
        EOD3
    4
    4
        EOD4
    3
    2
    Lymh node metastases at diagnosis
    Units: Subjects
        Yes
    8
    7
        No
    31
    29
    Gleason score at diagnosis (total)
    Units: Subjects
        Gleason 6
    3
    3
        Gleason 7
    9
    9
        Gleason 8
    9
    7
        Gleason 9
    17
    16
        Missing
    1
    1
    Time since histological confirmation of disease to trial entry
    Units: Years
        median (inter-quartile range (Q1-Q3))
    3.9 (2.1 to 6.7)
    3.9 (2.3 to 6.7)
    Time since confirmation of bone metastases to trial entry
    Units: Years
        median (inter-quartile range (Q1-Q3))
    2.2 (1.1 to 3.9)
    2.3 (1.1 to 4.3)
    Time since castration resistance to trial entry
    Units: Years
        median (inter-quartile range (Q1-Q3))
    1.1 (0.2 to 2.4)
    1.0 (0.1 to 2.1)

    End points

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    End points reporting groups
    Reporting group title
    55 kBq/kg Radium 223
    Reporting group description
    		 Participants in this arm were allocated to receive 55 kBq/kg of Radium 223. Allocation ratio between the 2 arms was 1:1. Treatment allocation was via minimisation with a random element; balancing factors included patient weight, total ALP and current bisphosphonate use. Dose allocation was not blinded. Patients received treatment with radium-223 at the allocated dose via IV administration every 4 weeks for up to 6 cycles.

    Reporting group title
    88 kBq/kg Radium 223
    Reporting group description
    		 Patients received treatment with radium-223 at the 88 kBq/kg via IV administration every 4 weeks for up to 6 cycles.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised

    Subject analysis set title
    Imaging study population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Excludes patients with key eligibility deviations

    Primary: DW-MRI response by global median ADC

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    End point title
    		 DW-MRI response by global median ADC [1]
    End point description
    End point type
    Primary
    End point timeframe
    From 1st injection until end of cycle 6.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was included because the primary endpoint was assessment of response rates with no formal comparison between groups.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 Imaging study population
    Number of subjects analysed
    19
    17
    36
    Units: Patients
        Responder
    6
    8
    14
        Non-responder
    13
    9
    22
    No statistical analyses for this end point

    Secondary: Qualitative DW-MRI response

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    End point title
    		 Qualitative DW-MRI response
    End point description
    End point type
    Secondary
    End point timeframe
    From 1st injection up to cycle 6.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 Imaging study population
    Number of subjects analysed
    19
    17
    36
    Units: Patients
        Response
    3
    5
    8
        Likely response
    6
    3
    9
        Stable
    6
    4
    10
        Likely progression
    2
    1
    3
        Progression
    2
    4
    6
    No statistical analyses for this end point

    Secondary: DW-MRI response according to mean ADC in 5 target lesions

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    End point title
    		 DW-MRI response according to mean ADC in 5 target lesions
    End point description
    End point type
    Secondary
    End point timeframe
    From 1st injection until end of cycle 6.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 Imaging study population
    Number of subjects analysed
    19
    17
    36
    Units: Patients
        Responder
    9
    14
    23
        Non-responder
    10
    3
    13
    No statistical analyses for this end point

    Secondary: Best qualitative response according to Fluoride PET-CT

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    End point title
    		 Best qualitative response according to Fluoride PET-CT
    End point description
    End point type
    Secondary
    End point timeframe
    From 1st injection until end of cycle 6.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 Imaging study population
    Number of subjects analysed
    19
    17
    36
    Units: Patients
        Partial response
    13
    8
    21
        Stable disease
    5
    7
    12
        Progressive disease
    1
    2
    3
    No statistical analyses for this end point

    Secondary: Best qualitative response according to Choline PET-CT

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    End point title
    		 Best qualitative response according to Choline PET-CT
    End point description
    End point type
    Secondary
    End point timeframe
    From 1st injection until end of cycle 6.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 Imaging study population
    Number of subjects analysed
    18 [2]
    17
    35 [3]
    Units: Patients
        Partial response
    5
    8
    13
        Stable disease
    12
    6
    18
        Progressive disease
    1
    3
    4
    Notes
    [2] - Choline PET-CT not available for 1 patient
    [3] - Choline PET-CT not available for 1 patient
    No statistical analyses for this end point

    Secondary: ALP response

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    End point title
    		 ALP response
    End point description
    Total ALP response is defined as ≥30% reduction of the blood level compared to the baseline value, assessed up to the end of treatment, confirmed by a second total-ALP value approximately 4 or more weeks later.
    End point type
    Secondary
    End point timeframe
    Measured up to the end of treatment.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 ITT Imaging study population
    Number of subjects analysed
    20
    19
    39
    36
    Units: Patients
        Confirmed responder
    13
    12
    25
    24
        Non-responder
    7
    7
    14
    12
    No statistical analyses for this end point

    Secondary: Time to ALP progression

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    End point title
    		 Time to ALP progression
    End point description
    Time to total ALP progression is defined as time from trial entry and first documented ALP progression. ALP progression is defined as: • In patients with no decline from baseline, ≥25% increase from baseline at least 12 weeks from baseline; • In patients with initial an decline from baseline, ≥25% increase from the nadir confirmed by a second value 3 or more weeks later.
    End point type
    Secondary
    End point timeframe
    From trial entry until ALP progression
    End point values
    		 ITT
    Number of subjects analysed
    39
    Units: Months
        median (confidence interval 95%)
    9.4 (7.0 to 12.4)
    No statistical analyses for this end point

    Secondary: PSA response

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    End point title
    		 PSA response
    End point description
    Total PSA response is defined as ≥50% reduction of the blood level compared to the baseline value, assessed up to the end of treatment, confirmed by a second total-ALP value approximately 3 or more weeks later. Cycle 1 PSA values are used as a baseline.
    End point type
    Secondary
    End point timeframe
    Measured up to the end of treatment
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 ITT Imaging study population
    Number of subjects analysed
    20
    19
    39
    36
    Units: Patients
        Confirmed responder
    2
    3
    5
    5
        Non-responder
    18
    16
    34
    31
    No statistical analyses for this end point

    Secondary: Time to PSA progression

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    End point title
    		 Time to PSA progression
    End point description
    End point type
    Secondary
    End point timeframe
    From trial entry to PSA progression
    End point values
    		 ITT
    Number of subjects analysed
    39
    Units: Months
        median (confidence interval 95%)
    4.2 (3.9 to 11.0)
    No statistical analyses for this end point

    Secondary: CTC response

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    End point title
    		 CTC response
    End point description
    Overall CTC response is defined as a CTC conversion (from >5 cells/7.5ml blood at baseline to <5 cells/7.5mls confirmed by 2 readings 4 weeks apart) or a CTC fall (at least 30% fall in CTCs compared to baseline).
    End point type
    Secondary
    End point timeframe
    Measured upto the end of treatment.
    End point values
    		 55 kBq/kg Radium 223 88 kBq/kg Radium 223 ITT Imaging study population
    Number of subjects analysed
    11 [4]
    6 [5]
    17 [6]
    16 [7]
    Units: Patients
        Responder
    5
    1
    6
    6
        Non-responder
    6
    5
    11
    10
    Notes
    [4] - Patients are required to have baseline CTC>5 to be evaluable for CTC response
    [5] - Patients are required to have baseline CTC>5 to be evaluable for CTC response
    [6] - Patients are required to have baseline CTC>5 to be evaluable for CTC response
    [7] - Patients are required to have baseline CTC>5 to be evaluable for CTC response
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From trial entry up to 4 weeks following treatment discontinuation. Adverse reactions were recorded until 1 year post treatment.
    Adverse event reporting additional description
    Any adverse events reported after baseline by at least 5% of the safety population (i.e. all those who received at least 1 dose of radium 223) are reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 All patients who received at least 1 dose of Radium 223

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 38 (10.53%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 38 (97.37%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    3
    Weight decreased
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    6
    Hypertension
         subjects affected / exposed
    28 / 38 (73.68%)
         occurrences all number
    84
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    24 / 38 (63.16%)
         occurrences all number
    52
    Leukopenia
         subjects affected / exposed
    10 / 38 (26.32%)
         occurrences all number
    18
    Lymphopenia
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    11
    Neutropenia
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    9
    Pancytopenia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 38 (23.68%)
         occurrences all number
    24
    Gait disturbance
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    14 / 38 (36.84%)
         occurrences all number
    23
    Dyspepsia
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Renal and urinary disorders
    Lower urinary tract symptoms
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    13
    Back pain
         subjects affected / exposed
    14 / 38 (36.84%)
         occurrences all number
    35
    Bone pain
         subjects affected / exposed
    15 / 38 (39.47%)
         occurrences all number
    27
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 38 (13.16%)
         occurrences all number
    6
    Musculoskeletal pain
         subjects affected / exposed
    5 / 38 (13.16%)
         occurrences all number
    7
    Neck pain
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    6
    Pain in extremity
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Pelvic fracture
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Spinal fracture
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 38 (23.68%)
         occurrences all number
    22
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2016
    Change in dose from 50kBq/kg to 55kBq/kg and from 80kBq/kg to 88kBq/kg following world-wide NIST primary reference standard revision. Inclusion criteria changed from age ≥16 years to age ≥18 years to reflect ARSAC guidance
    01 Oct 2018
    Addition of a new objective, endpoints statistical considerations and follow up schedule to investigate the incidence of fractures post radium-223. Clarification of existing statistical and imaging considerations.
    15 Oct 2021
    Inclusion of additional exploratory endpoint related to overall survival and collection of survival data beyond 1 year.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37788117
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