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    Clinical Trial Results:
    A Phase II Study of Radium-223 in Combination with Enzalutamide in Progressive Metastatic Castrate-Resistant Prostate Cancer

    Summary
    EudraCT number
    		 2013-004850-97
    Trial protocol
    		 IE  
    Global end of trial date
    23 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jan 2023
    First version publication date
    08 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13-21
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02225704
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cancer Trials Ireland
    Sponsor organisation address
    RCSI House, 121 St. Stephen’s Green, Dublin 2, Ireland, D02 H903
    Public contact
    Head of Clinical Operations, Cancer Trials Ireland, +353 16677211, regulatory@cancertrials.ie
    Scientific contact
    Head of Clinical Operations, Cancer Trials Ireland, +353 16677211, regulatory@cancertrials.ie
    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
    04 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To determine the safety and tolerability of Radium-223 when administered in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer.
    Protection of trial subjects
    The study was conducted in accordance with the EU Directive 2001/20/EC and International Conference on Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s). Site monitoring was performed from the time of initiation until study close-out and complied with EU directive 2001/20/EC and ICH GCP (CPMP/ICH/135/95) regulations.
    Background therapy
    		 All patients had concurrent use of an agent for medical castration (e.g. Gonadotropin releasing hormone (GnRH) analogue).
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    04 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    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)
    14
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study recruited a total of 47 patients. The first patient was enrolled in August 2015 and the last patient was recruited in July 2017.

    Pre-assignment
    Screening details
    		 Patients recruited to the study will have received a diagnosis for progressive metastatic castrate-resistant prostate cancer and must fulfil all inclusion criteria and none of the exclusion criteria outlined in protocol.

    Pre-assignment period milestones
    Number of subjects started
    		 45
    Number of subjects completed
    		 45

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This study was a single arm non blinded study

    Arms
    Arm title
    		 Single Arm
    Arm description
    		 Single arm study of the combination of Radium-223 dichloride in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Radium -223 dichloride
    Investigational medicinal product code
    BAY 88-8223,
    Other name
    Xofigo
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    55kBq/kg slow bolus IV injection on Day 1 of every four week cycle, for a maximum of 6 cycles

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Xtandi
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    (160mg po daily; (4 x 40 mg capsules)) until disease progression, unacceptable toxicity, consent withdrawal or withdrawal for any other reason, or study close

    Number of subjects in period 1
    		Single Arm
    Started
    45
    Completed
    10
    Not completed
    35
         Died on-study (all in follow-up)
    22
         Consent withdrawn by subject
    2
         Study close-out
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 45 45
    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)
    		 14 14
        From 65-84 years
    		 31 31
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 68.0 (51 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 45 45
    Ethnic Origin
    Units: Subjects
        Caucasion
    		 45 45
    Subject analysis sets

    Subject analysis set title
    Overall Trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This subject analysis set is being created as a workaround to allow reporting of a statistical analysis on a single arm study.

    Subject analysis sets values
    		 Overall Trial
    Number of subjects
    45
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    14
        From 65-84 years
    31
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    68 (51 to 79)
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnic Origin
    Units: Subjects
        Caucasion

    End points

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    End points reporting groups
    Reporting group title
    Single Arm
    Reporting group description
    		 Single arm study of the combination of Radium-223 dichloride in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer.

    Subject analysis set title
    Overall Trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This subject analysis set is being created as a workaround to allow reporting of a statistical analysis on a single arm study.

    Primary: The incidence of grade 3 or higher adverse events during the period of combination therapy will be recorded and graded according to the NCI - CTCAE criteria, version 4.

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    End point title
    		 The incidence of grade 3 or higher adverse events during the period of combination therapy will be recorded and graded according to the NCI - CTCAE criteria, version 4.
    End point description
    The primary endpoint is the grade 3/4 toxicity rate for the combination therapy, defined as the incidence of patients experiencing an adverse event of grade 3 toxicity or higher during the period of combination therapy.
    End point type
    Primary
    End point timeframe
    From date of registration to the date of clinical /radiological disease progression or death, whichever is reported first.
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: Adverse Events
    45
    45
    Statistical analysis title
    		 Incidence rate of G3+ Combination Therapy AEs
    Statistical analysis description
    The grade 3/4 toxicity rate presented as the percentage of patients in the safety population who experienced a grade 3 or higher toxicity during combination therapy, together with the accompanying two-sided 90% and 95% confidence intervals, calculated using the normal approximation.
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Incidence rate and confidence interval
    Parameter type
    		 Incidence rate
    Point estimate
    31.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 19.8
         upper limit
    		 42.5
    Notes
    [1] - Incidence rate and confidence interval

    Secondary: Time to clinical/radiological progression

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    End point title
    		 Time to clinical/radiological progression
    End point description
    Time to clinical/radiological progression (as measured according to PCWG2 and RECIST 1.1 criteria). Clinical progression is defined as evidence of progression or recurrence on imaging, clinical examination, development of cancer related symptoms or treatment withdrawal for reasons of clinical progression
    End point type
    Secondary
    End point timeframe
    From start of treatment to Clinical/Radiological Progression
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: Months
    45
    45
    Statistical analysis title
    		 Time to Clinical/Radiological Progression
    Statistical analysis description
    For the ITT set of 45 patients, 24 patients (54.5%) progressed and 20 patients (45.5%) were censored at the date when last known to be progression-free, or the date of start of new anti-cancer treatment (including restart of enzalutamide) if earlier. One patient did not have any post-screening scans.
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Median
    Point estimate
    28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.5
         upper limit
    		 61.2
    Notes
    [2] - the Kaplan-Meier (1958) analysis for clinical/radiological PFS

    Secondary: Time to PSA progression

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    End point title
    		 Time to PSA progression
    End point description
    The objective time to PSA (prostate specific antigen) progression of patients treated with Radium-223 in combination with enzalutamide in progressive metastatic castrate-resistant prostate cancer. Progression will be assessed in accordance with recommendations by the Prostate Cancer Working Group (PCWG2) criteria.
    End point type
    Secondary
    End point timeframe
    From registration to PSA progression
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: months
    45
    45
    Attachments
    		 time to PSA Progression
    Statistical analysis title
    		 Time to PSA Progression
    Statistical analysis description
    For the ITT set of 45 patients, 36 patients (80%) progressed, and 9 patients (20%) were censored at the date when last known to be progression-free, or the date of start of new anti-cancer treatment (including restart of enzalutamide) if earlier. Median time to PSA progression was 18.1 months with 95% CI of [12.7 – 22.6] months. The PFS rate at 12 months was estimated at 64.9% with 95% CI of [48.6 – 77.2].
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    18.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.7
         upper limit
    		 22.6
    Notes
    [3] - the Kaplan-Meier analysis

    Secondary: PSA response (50% reduction from baseline)

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    End point title
    		 PSA response (50% reduction from baseline)
    End point description
    PSA Response is defined as 2 consecutive assessments at least 3 weeks apart with a reduction of at least 50% from baseline.
    End point type
    Secondary
    End point timeframe
    PSA assessment every four weeks for a maximum of 6 cycles and every six weeks after until disease progression, unacceptable toxicity, consent withdrawal or withdrawal for any other reason, or study close
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: patients
    45
    45
    Statistical analysis title
    		 PSA Response
    Statistical analysis description
    PSA Response, defined as 2 consecutive assessments at least 3 weeks apart with a reduction of at least 50% from baseline for the ITT set. A total of 43 patients (95.6%) responded, with 95% CI [89.5% - 100%].
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 40
         upper limit
    		 45
    Notes
    [4] - PSA response (50% reduction from baseline) presented as the percentage of patients with response, together with the accompanying two-sided 95% confidence interval, calculated using the normal approximation.

    Secondary: Change in alkaline phosphatase

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    End point title
    		 Change in alkaline phosphatase
    End point description
    End point type
    Secondary
    End point timeframe
    Alkaline phosphatase assessment every four weeks for a maximum of 6 cycles and every six weeks after until disease progression, unacceptable toxicity, consent withdrawal or withdrawal for any other reason, or study close.
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: IU/L
    45
    45
    Statistical analysis title
    		 Change in alkaline phosphatase
    Statistical analysis description
    The median baseline level was 99.0 IU/L (range of 39 – 964), which reduced to 66.5 IU/L (range of 30 – 107) after 6 cycles of study treatment. The median level at the end of study treatment was 90.5 IU/L (range of 34 – 534).
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    66.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30
         upper limit
    		 107
    Notes
    [5] - Descriptive statistics presented for change in alkaline phosphatase from baseline

    Secondary: Time to first skeletal-related event

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    End point title
    		 Time to first skeletal-related event
    End point description
    Skeletal-related events are defined as the first event of: -the first use of external-beam radiation therapy to relieve skeletal symptoms, -new pathologic vertebral or non-vertebral bone fractures, -spinal cord compression, or -tumor-related orthopedic surgical intervention For the ITT set of 45 patients, 8 patients (17.8%) experienced an SRE and the remaining 37 patients (82.2%) were censored at the end of the 2 years follow up period. Because of the small number of events, the median time to first SRE and 95% CI were not estimable.
    End point type
    Secondary
    End point timeframe
    The period for the reporting of all serious and non-serious skeletal related events was from date of consent to until the end of the 2 years follow-up period or until study close.
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: months
    45
    45
    No statistical analyses for this end point

    Secondary: Pain assessment (Brief Pain Inventory-Short Form)

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    End point title
    		 Pain assessment (Brief Pain Inventory-Short Form)
    End point description
    The Brief Pain Inventory-Short Form should be completed prior to any other study related procedures. Individual questions were scored on a scale of 0 – 10, where 0 represented no pain and 10 represented pain as bad as could be imagined.
    End point type
    Secondary
    End point timeframe
    Pain assessment (Brief Pain Inventory-Short Form) every four weeks for a maximum of 6 cycles and every six weeks after until disease progression, unacceptable toxicity, consent withdrawal or withdrawal for any other reason, or study close.
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: score
    45
    45
    Statistical analysis title
    		 Pain assessment
    Statistical analysis description
    Descriptive statistics will be presented for change in pain from baseline as assessed by the Brief Pain Inventory-Short Form. Pain severity score, calculated as the mean of the 4 individual pain question scores, (only calculated where >50%, or at least 3, of the individual scores are non-missing). The median severity score at baseline was 1.8 (range of 0 – 8), which was largely unchanged at median 1.9 (range of 0 – 6) after 6 cycles of study treatment.
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 8
    Notes
    [6] - Descriptive statistics

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    From the date of registration to the date of death from any cause. Patients lost to follow up or those with no death recorded on the day the database is finalised will be censored on the date last known to be alive.
    End point values
    		 Single Arm Overall Trial
    Number of subjects analysed
    45
    45
    Units: months
    45
    45
    Attachments
    		 Untitled (Filename: Overall survival.png)
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    For the ITT set of 45 patients, 22 patients (48.9%) died on study (20 from disease progression and 2 from adverse events unrelated to study treatment) and 23 patients (51.1%) were censored at the date when last known to be alive. Median time to death was 51.1 months. Less than 50% of the patients had died and the 95% CI was not fully estimable, the lower bound was 35.3 months.
    Comparison groups
    Single Arm v Overall Trial
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    51.1
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 35.3
         upper limit
    		 -
    Notes
    [7] - the Kaplan-Meier analysis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of patient's informed consent and up to 30 days after the end of study treatment.
    Adverse event reporting additional description
    The intensity of the adverse events recorded as per CTCAE v4.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Single arm study of the combination of Radium-223 dichloride and enzalutamide for a maximum of 6 cycles and enzalutamide alone after until disease progression, unacceptable toxicity, consent withdrawal or withdrawal for any other reason, or study close, in progressive metastatic castrate-resistant prostate cancer.

    Serious adverse events
    		 Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 45 (44.44%)
         number of deaths (all causes)
    22
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal gland cancer metastatic
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Carcinoid tumour of the appendix
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal cell carcinoma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Parkinsonism
    Additional description: Investigaton of Parkinson's symptoms
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 45 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Rectal neoplasm
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Metastases to spinal cord
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 45 (26.67%)
         occurrences all number
    45
    Hot flush
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    7
    Haemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Skin neoplasm excision
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    5
    Skin graft
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Transurethral prostatectomy
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Suprapubic pain
    Additional description: Suprapubic tenderness
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    7
    Chest pain
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    30 / 45 (66.67%)
         occurrences all number
    55
    Oedema
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Application site erythema
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    6
    Asthenia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Swelling
    Additional description: Swelling in groin
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Injection site pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Feeling hot
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Infusion site extravasation
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Chest discomfort
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Injection site reaction
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Swelling face
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Localised oedema
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Injection site haemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Injection site nodule
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Prostate tenderness
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gynaecomastia
         subjects affected / exposed
    7 / 45 (15.56%)
         occurrences all number
    7
    Pruritus genital
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pelvic pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Testicular pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Balanoposthitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    5
    Nasal discomfort
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Pulmonary infarction
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Dyspnoea exertional
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Productive cough
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Pulmonary mass
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pulmonary embolism
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Depressed mood
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    6
    Insomnia
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    6
    Confusional state
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Tearfulness
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Nightmare
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Weight increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    12 / 45 (26.67%)
         occurrences all number
    21
    Blood magnesium decreased
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    White blood cell count decreased
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    15
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    10
    Intraocular pressure increased
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Blood urine present
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Blood glucose increased
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Blood cholesterol increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Blood folate decreased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Blood potassium decreased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Blood creatinine increased
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    7
    C-reactive protein increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Blood iron decreased
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Blood urea increased
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Blood calcium increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pulse absent
    Additional description: Pedal pulse absent right foot
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Blood potassium increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fractured sacrum
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Acetabulum fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Thyroid gland injury
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Scratch
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Rib fracture
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    7
    Lumbar vertebral fracture
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    5
    Fall
         subjects affected / exposed
    7 / 45 (15.56%)
         occurrences all number
    8
    Ligament sprain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Tibia fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ankle fracture
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Infusion related reaction
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Forearm fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Femur fracture
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Radiation mucositis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ligament rupture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Skin wound
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hyphaema
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Skin laceration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Animal bite
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Toxicity to various agents
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Cardiac failure
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Conduction disorder
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Bradycardia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Bundle branch block right
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    7
    Burning sensation
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    12 / 45 (26.67%)
         occurrences all number
    17
    Memory impairment
    Additional description: Short memory disturbance
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    5
    Lumbosacral radiculopathy
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ageusia
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Dyskinesia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    3
    Restless legs syndrome
         subjects affected / exposed
    8 / 45 (17.78%)
         occurrences all number
    8
    Amnesia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Hypoaesthesia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    4
    Disturbance in attention
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Neuropathy peripheral
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Presyncope
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Sciatica
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Parkinson's disease
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Dysaesthesia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 45 (22.22%)
         occurrences all number
    16
    Neutropenia
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    21
    Thrombocytopenia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Tinnitus
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Excessive cerumen production
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ear pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Deafness
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Vitreous floaters
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    26 / 45 (57.78%)
         occurrences all number
    53
    Anorectal discomfort
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    11 / 45 (24.44%)
         occurrences all number
    11
    Abdominal pain
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    24 / 45 (53.33%)
         occurrences all number
    32
    Dyspepsia
    Additional description: Indigestion
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Loose tooth
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 45 (13.33%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    8 / 45 (17.78%)
         occurrences all number
    13
    Abdominal pain upper
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    7
    Toothache
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Rectal haemorrhage
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Tongue blistering
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Abdominal discomfort
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Oral pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Abdominal pain lower
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    4
    Frequent bowel movements
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gingival pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Noninfective gingivitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Tongue discolouration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Tongue haemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Barrett's oesophagus
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Anal haemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    6
    Rash
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Skin lesion
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Petechiae
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hidradenitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Skin discolouration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Rash papular
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Ingrowing nail
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Nail disorder
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Renal and urinary disorders
    Pollakiuria
    Additional description: Increased urinary frequency
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Bladder spasm
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Dysuria
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Urinary retention
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Nocturia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Haematuria
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Bladder hypertrophy
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Micturition urgency
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hydroureter
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hydronephrosis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Adrenal mass
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    18 / 45 (40.00%)
         occurrences all number
    30
    Pain in extremity
         subjects affected / exposed
    11 / 45 (24.44%)
         occurrences all number
    18
    Bone pain
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    12
    Myalgia
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Arthralgia
         subjects affected / exposed
    22 / 45 (48.89%)
         occurrences all number
    31
    Sacral pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Pain in jaw
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    5
    Arthritis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Muscular weakness
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Osteoporotic fracture
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Pubic pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Plantar fasciitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Neck pain
         subjects affected / exposed
    5 / 45 (11.11%)
         occurrences all number
    7
    Groin pain
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Pathological fracture
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 45 (8.89%)
         occurrences all number
    5
    Furuncle
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Localised infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Eye infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 45 (17.78%)
         occurrences all number
    13
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Stoma site cellulitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    3
    Gingivitis
         subjects affected / exposed
    3 / 45 (6.67%)
         occurrences all number
    9
    Osteomyelitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Penile infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Lower respiratory tract infection
         subjects affected / exposed
    9 / 45 (20.00%)
         occurrences all number
    11
    Conjunctivitis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Candida infection
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Tinea pedis
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Skin infection
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Ludwig angina
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 45 (31.11%)
         occurrences all number
    18
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Appetite disorder
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 45 (4.44%)
         occurrences all number
    3
    Iron deficiency
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    1
    Dehydration
         subjects affected / exposed
    1 / 45 (2.22%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Oct 2015
    Incorporation of the requirement to implement National Institute of Standards and Technology (NIST) update changes in regards to Radium 223 dose, Reference Safety information updated for both study drugs. Translational section revised to increase in blood volume collected. Inclusion and exclusion criteria amended due to reference safety information updates and CHAARTED trial. Included administrative changes and an update to the statistical considerations and Safety
    17 May 2018
    Administrative changes to include update to sponsor's name, staff changes and removal of a study site. Also included a change to Radium dose as per NIST update and addition of 2 study objectives to correspond to 2 listed study endpoints. Update to reference safety data for Xtandi and Radium-223. Update to estimated study completion date. Changes of wording to further clarify protocol details. Change of AE reporting timeline from 28 to 30 days after study treatment and wording changes to clarify reporting.
    22 Nov 2019
    Changes in wording to define clinical progression - wherever radiological progression was mentioned, this is replaced with clinical/radiological progression. Clarification added that if patients recommence Enzalutamide in the follow up period, this will be considered as a new treatment.
    25 Jan 2021
    Amendment to the protocol to facilitate closure of the trial. Enzalutamide is considered standard of care treatment in this setting and is available to patients outside of this clinical trial. The protocol is amended so that all patients on enzalutamide treatment will discontinue study treatment and will complete a post-treatment withdrawal visit 30 to 42 days after the last dose and will be taken off study. These patients may continue with enzalutamide treatment outside of the study as per standard of care. Patients in follow up for survival at study close will cease all follow up visits/calls.

    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/34512801
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