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    Clinical Trial Results:
    Neo-adjuvant Androgen Deprivation Therapy, Pelvic Radiotherapy and RADium-223 for new presentation T1-4 N0/1 M1B adenocarcinoma of prostate (ADRRAD Trial)

    Summary
    EudraCT number
    		 2014-000273-39
    Trial protocol
    		 GB  
    Global end of trial date
    04 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Aug 2023
    First version publication date
    19 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14095JOS-SS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Belfast Health and Social Care Trust
    Sponsor organisation address
    East Podium, C floor, Belfast, United Kingdom, BT9 7AB
    Public contact
    Prof Joe O'Sullivan, Belfast Health and Social Care Trust, 0044 2895048349, rebecca.gallagher@belfasttrust.hscni.net
    Scientific contact
    Prof Joe O'Sullivan, Belfast Health and Social Care Trust, 0044 2895048349, rebecca.gallagher@belfasttrust.hscni.net
    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
    07 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the safety, toxicity and feasibility of the combination of ADT + Radium-223 + IMRT in men with castration sensitive, M1b metastatic prostate cancer with a view to larger future randomised trials.
    Protection of trial subjects
    The trial was comprehensively discussed with all participants in advance of informed consent. All participants were screened for eligibility prior to registration on the trial. Adverse events were assessed at baseline, weekly during Radiation and Radium-223 treatment and six weeks post treatment. Adverse events were followed up until resolution. Trial safety was part of the remit of the Trial Management Group meeting which were held monthly during treatment and 3-monthly during follow up. An Independent Data Monitoring Committee was appointed to study safety and efficacy data during the study. Safety and efficacy data was reviewed on a periodic basis, approximately every 6 months from enrolment of the first patient until the end of the study. Following all Independent Data Monitoring Committee meetings, recommendations were provided to the Trial Management Group and Trial Sponsor.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jan 2016
    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: 30
    Worldwide total number of subjects
    30
    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)
    19
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Thirty patients were recruited to the study. Eligible patients had been diagnosed with histologically confirmed de-novo bone metastatic hormone sensitive prostate cancer and had an ECOG performance status of 0-1. All participants had at least three bone metastases demonstrated on bone scan and no visceral metastases on CT/thorax/abdo/pelvis

    Pre-assignment
    Screening details
    		 Thirty three patients were consented to the study, thirty one, of which, were found to be eligible and were registered on study. Thirty patients received study treatment and were deemed evaluable

    Pre-assignment period milestones
    Number of subjects started
    		 31 [1]
    Number of subjects completed
    		 30

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Disease progression: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Thirty one patients were registered on study. However, one patient was withdrawn from study prior to treatment initiation due to disease progression.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    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
    The dose regimen for Xofigo is an activity if 55kBq per Kg body weight, given at 4 week intervals for six injections

    Investigational medicinal product name
    Zoladex 3.6mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One 3.6mg depot of Zoladex injected subcutaneously into the anterior abdominal wall every 28 days.

    Investigational medicinal product name
    Zoladex LA 10.8mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One depot of Zoladex LA injected subcutaneously into the anterior abdominal wall every 12 weeks

    Investigational medicinal product name
    Decapeptyl SR 3mg
    Investigational medicinal product code
    Other name
    Triptorelin acetate
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One intramuscular injection administered every 4 weeks

    Investigational medicinal product name
    Decapeptyl SR 11.25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One intramuscular injection administered every 3 months

    Investigational medicinal product name
    Prostap SR DCS 11.25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The usual recommended dose is 11.25mg presented as a three month depot injection and administered as a single subcutaneous injection at intervals of 3 months

    Investigational medicinal product name
    PROSTAP SR DCS 3.75mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for prolonged-release suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    3.75 mg presented as a one month depot injection and administration as a single subcutaneous or intramuscular injection every month.

    Number of subjects in period 1
    		Treatment
    Started
    30
    Completed
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 11 11
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (45 to 82) -
    Gender categorical
    Units: Subjects
        Male
    		 30 30

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Primary: Gastrointestinal (GI) adverse events

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    End point title
    		 Gastrointestinal (GI) adverse events [1]
    End point description
    Within the gastrointestinal domain, the most frequent adverse event observed was diarrhoea. Twenty five patients (83.3%) experienced diarrhoea, which was grade 1-2 in all patients. There were no grade 3, 4 or 5 gastrointestinal events observed during the conduct of the study.
    End point type
    Primary
    End point timeframe
    Adverse events were assessed from Informed Consent until 8 weeks post last radium-223 infusion.
    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: In this Phase I/II trial, gastrointestinal adverse events are expressed as rates.
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Number of patients
        GI Toxicity Grade 1
    22
        GI Toxicity Grade 2
    7
        GI Toxicity Grade 3
    0
    No statistical analyses for this end point

    Primary: Genito-urinary adverse events

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    End point title
    		 Genito-urinary adverse events [2]
    End point description
    During the six weeks of treatment and 8-week follow up period, grade 1 to grade 3 adverse events were observed in the genito-urinary (GU) domain. Seventeen patients (56.7%) experienced dysuria, with one patient experiencing a grade 3. One additional patient experienced a grade 3 urinary tract infection (UTI) which responded to antibiotic therapy.
    End point type
    Primary
    End point timeframe
    Adverse events were assessed from informed consent until 8 weeks after final radium-223 infusion using common Terminology Criteria for Adverse event (CTCAE) v 4.03
    Notes
    [2] - 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: In this Phase I/II trial, Genito-urinary adverse events are expressed as rates.
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Number of patients
        Genito-urinary adverse events grade 1
    18
        Genito-urinary adverse events grade 2
    8
        Genito-urinary adverse events grade 3
    1
    No statistical analyses for this end point

    Primary: Quality of Life: bowel and urinary domains

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    End point title
    		 Quality of Life: bowel and urinary domains [3]
    End point description
    Mean domain scores were calculated. There was a significant fall in bowel and urinary scores between screening and the start of cycle 3, that is, during the concurrent phase of treatment (mean bowel score at screening = 95.10, mean bowel score C3 = 81.0 P<0.001; mean urinary score at screening was 90.48 compared to the mean urinary score at cycle 3 which was 79.02 P = 0.003. These scores recover such that there is no significant difference between scores at screening and scores at the end of trial in either domain.
    End point type
    Primary
    End point timeframe
    Patients completed EPIC scores at screening, q4 weekly during radium-223 treatment, at 8 weeks post final radium-223 treatment and six months later at the end of study.
    Notes
    [3] - 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: Mean domain scores were calculated with P values reported in the description.
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Change in mean EPIC Scores
    number (not applicable)
        Mean bowel scores at screening
    95.10
        Mean bowel scores at cycle 3
    81.0
        Mean urinary scores at screening
    90.48
        Mean urinary scores at cycle 3
    79.02
    No statistical analyses for this end point

    Secondary: Tumour response

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    End point title
    		 Tumour response
    End point description
    Scans were compared pairwise within each patient, screening to post 6 cycle radium 223 and post cycle 6 to end of study. Scans were reported in categorial fashion based on overall disease behaviour showing: Tumour Burden (TB) increase, TB stable, TB reduction and TB resolution. Tumour burden increase was identified by a 25% increase in size of the lesion. The development of peri-lesional edema was also noted as a likely indicator of increasing tumour burden. TB reduction was indicated by a 50% decrease in the size of the lesion with replacement of the peripheral margin of the lesion by normal fatty marrow. Loss of peri-lesion edema was also noted as a likely indicator of tumour response. Stability fell between these definitions. TB resolution was indicated by complete resolutions of lesions.
    End point type
    Secondary
    End point timeframe
    Patients had a whole body MRI performed at screening, 8 weeks post final radium-223 infusion and again at 6 months post final radium-223 infusion.
    End point values
    		 Treatment
    Number of subjects analysed
    28
    Units: Number of patients
        Tumour burden resolved at 6 months
    6
        Tumour burden reduced at 6 months
    16
        Tumour burden stable at 6 months
    2
        Tumour burden increased at 6 months
    4
        Tumour burden resolved at 12 months
    7
        Tumour burden reduced at 12 months
    9
        Tumour burden stable at 12 months
    1
        Tumour burden increased at 12 months
    11
    No statistical analyses for this end point

    Secondary: Alkaline phosphatase (ALP) Response

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    End point title
    		 Alkaline phosphatase (ALP) Response
    End point description
    ALP was measured as a marker of biochemical response and bone health. ALP was expressed as means per timepoint. Between screening and cycle 6 Radium-223 (6 months), ALP fell in 27 patients ( 90%). This trend reverses 6 months later, at end of study, where fifteen patients were shown to have a decrease in ALP at this timepoint compared to screening.
    End point type
    Secondary
    End point timeframe
    All patients had Alkaline Phosphatase (ALP) measured q4 weekly during treatment, at 8 weeks post final Radium-223 injection and again at end of study (6 months post final Radium-223 injection).
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Number of patients
        Decrease in ALP at 6 months
    27
        Decrease in ALP at 12 months
    15
    No statistical analyses for this end point

    Secondary: Symptomatic Skeletal Events

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    End point title
    		 Symptomatic Skeletal Events
    End point description
    During the trial, no patient received bone health treatment, as was standard for metastatic hormone sensitive prostate cancer patients at this time. In terms of fractures, in total 8 patients (26.7%) experienced at least one malignant fracture, 3 (10%) patients experienced at least one fragility fracture and 1 patient (3.3%) experienced two traumatic fractures. Nine courses of palliative radiotherapy were delivered, eight for bone pain and one for spinal cord compression.
    End point type
    Secondary
    End point timeframe
    Patients were followed up for skeletal outcomes for 2 years following treatment.
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Number of patients
    6
    No statistical analyses for this end point

    Secondary: Alkaline phosphatase response

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    End point title
    		 Alkaline phosphatase response
    End point description
    Between screening and cycle 6 of radium-223, ALP fell in27 patients (90%). This trend reverses 6 months later at the end of study, at this time point 15 patients (50%) have shown ALP increase relative to screening.
    End point type
    Secondary
    End point timeframe
    Alkaline phosphatase (ALP) was measured q4 weekly during treatment, at 8 weeks post final radium infusion and again at end of study, 6 months post final radium-223 infusion
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Number of patients
    27
    No statistical analyses for this end point

    Secondary: Biochemical progression free survival

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    End point title
    		 Biochemical progression free survival
    End point description
    Time to PSA progression was defined by PCWG2 criteria; 25% or greater increase and an absolute increase of 2ng/mL or more from the nadir. Survival times were calculated from the time of administration of first pretrial docetaxel for those patients who received it or trial registration for patients in whom docetaxel was contraindicated. This accounts for the mix of patients, 28 of whom were post docetaxel and 2 of whom were not. Median progression free survival was calculated by Kaplan-Meier methods. Median overall survival had not yet been reached.
    End point type
    Secondary
    End point timeframe
    Patients has PSA measured q4 weekly during treatment, at 8 weeks post final radium-223 infusion and again at end of study, 6 months post final radiun-223 infusion.
    End point values
    		 Treatment
    Number of subjects analysed
    30
    Units: Months
        number (not applicable)
    20.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were reported from consent to 2 months post last Radium-223 injection.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 -

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Chest pain-cardiac
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Cystitis non-infective
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    Vascular disorders
    HOT FLASHES
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    POSTURAL HYPOTENSION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    THROMBOEMBOLIC EVENT (PULMONARY EMBOLUS)
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 30 (60.00%)
         occurrences all number
    18
    Head cold
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    INSOMNIA
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    LOW MOOD
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Investigations
    GGT INCREASED
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    22 / 30 (73.33%)
         occurrences all number
    43
    PLATELET COUNT DECREASED
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    12
    WEIGHT LOSS
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    WHITE BLOOD CELL DECREASED
         subjects affected / exposed
    27 / 30 (90.00%)
         occurrences all number
    68
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    UREA INCREASED
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    RIGHT ELBOW TRAUMATIC FRACTURE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Cardiac disorders
    Chest pain-cardiac
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LETHARGY
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    PERIPHERAL NEUROPATHY
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PRESYNCOPE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    SYNCOPE
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 30 (46.67%)
         occurrences all number
    18
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    11
    Abdominal cramps
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Abdominal discomfort
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Bowel Frequency
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    22 / 30 (73.33%)
         occurrences all number
    41
    Faecal urgency
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Flatulence
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LEFT SIDED ABDOMINAL DISCOMFORT
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LOOSE STOOL
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    5
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    7
    VOMITING
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    ABDOMINAL PAIN
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    BOWEL URGENCY
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    RECTAL URGENCY
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    INSECT BITE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PSOARIATIC FLARE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    SKIN REACTION
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    SKIN RASH
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    CYSTITIS NON-INFECTIVE
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    5
    DYSURIA
         subjects affected / exposed
    15 / 30 (50.00%)
         occurrences all number
    18
    HAEMATURIA
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    NOCTURIA
         subjects affected / exposed
    18 / 30 (60.00%)
         occurrences all number
    26
    URINARY FREQUENCY
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    10
    URINARY HESITANCY
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    URINARY INCONTINENCE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    URINARY URGENCY
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    10
    ARTHRITIS RIGHT HAND
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    BACK PAIN
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    5
    BONE PAIN LUMBAR SPINE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    ENDPLATE FRACTURE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    IMPENDING SPINAL CORD COMPRESSION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    INSUFFICIENCY FRACTURE SACRAL ALA
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    KNEE PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LEFT ANTERIOR CHEST DISCOMFORT
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LEFT ELBOW PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LEFT HUMERAL PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LEFT SHOULDER PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    LOWER BACK PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    OSTEOPATHIC FRACTURE T7
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PAIN RIGHT GROIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    PATHOLOGICAL FRACTURE AT T4 AND L4
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL FRACTURE OF 5TH RIB
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL FRACTURE OF L1, L2 AND L5
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL FRACTURE OF T10, L3 AND L4
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL FRACTURE OF T3
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL FRACTURE OF T4 AND L1
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL FRACTURE OF T8
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    PATHOLOGICAL VERTEBRAL FRACTURES
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    RIB INJURY
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    RIGHT HIP PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    RIGHT PELVIC PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    THUMB PAIN
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Infections and infestations
    BRONCHIAL INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    CORYZAL INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Lung infection
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    ORAL HERPES ZOSTER
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    SHINGLES
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    SKIN INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    2
    CHEST INFECTION
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    ANOREXIA
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    HYPOPHOSPHATEMIA
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2015
    The protocol was amended to reflect the US National Institute of Standards and Technology update of the reference standard resulting in the numerical description of the patient dose being adjusted from 50 kBq/kg to 55 kBq/kg.
    13 Apr 2016
    This amendment included the following:-The protocol was updated to include exclusion criteria to ensure that any patients receiving chemotherapy prior to trial entry had a suitable delay, to ensure bone marrow recovery before receiving radionuclide in this study. This was in response to a UK change in standard of care where docetaxel treatment became standard of care for men with newly diagnosed hormone sensitive metastatic prostate cancer, where eligible. Also, the US National Institute of Standards and Technology updated the reference standard resulting in the numerical description of the patient dose being adjusted from 50 kBq/kg to 55 kBq/kg , the patient information sheet was updated to include this. In addition the RSI for the study was updated.
    06 Oct 2016
    The protocol was amended to update the requirements for extra blood to be taken for an exploratory end point.
    15 Mar 2017
    This substantial amendment included the following: The protocol was updated to change the PSA threshold from 5ng/mL to 20ng/mL to allow patients to progress into the radiation treatment phase of the study. In addition, overall survival was added as an exploratory end point. Furthermore, the recruitment end date and study end date was extended. This amendment also included updates to the Reference Safety Information for the study.
    21 Sep 2018
    The ADRRAD protocol also underwent a substantial protocol amendment in response to the issue of the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommendations (dated 13 July 2018) restricting the use of Xofigo®. The recommendations were issued following the early unblinding of the ERA-223 randomised controlled trial, combining radium-223 with abiraterone due to concerns about increase of fracture rate and deaths in the combination group. In response to this, the ADRRAD study was amended to include collection of data on bone health up to 24 months post radium-223 treatment initiation. In addition, the patient information sheet was updated to include information on the risk of Xofigo® when combined with abiraterone. Also, there was a update to the Reference Safety Information for one of the LHRH analogues used in the study. The study recruitment date was extended.
    16 Sep 2019
    There was an update to the reference Safety Information for Xofigo.

    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/34187853
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