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    Clinical Trial Results:
    IP4- CHRONOS: Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer

    Summary
    EudraCT number
    		 2019-001365-32
    Trial protocol
    		 GB  
    Global end of trial date
    13 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Dec 2024
    First version publication date
    20 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    19CX5006
    Additional study identifiers
    ISRCTN number
    		 ISRCTN17796995
    US NCT number
    		 NCT04049747
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Charing Cross Hospital Campus, Fulham Palace Road,, London, United Kingdom, W6 8RF
    Public contact
    Professor Hashim Ahmed, Imperial College London, hashim.ahmed@imperial.ac.uk
    Scientific contact
    Professor Hashim Ahmed, Imperial College London, hashim.ahmed@imperial.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Our initial CHRONOS trial will be a pilot study. If successful, we will apply for funding for a full main study which will run through if and when funding is approved. We have therefore described the objectives for both phases of CHRONOS, and for both CHRONOS-A and CHRONOS-B. Pilot study: 1)To determine patient acceptance to randomisaton 2) To coniduct an embedded qualitative study of patient and clinician acceptance and experience of the linked RCT CHRONOS design 3) To establish the feasibility of an economic evaluation alongside the main trial 4) To determine the acceptability and completeness of resource use and utility measures (EQ- 5D- 5L) 5) To identify the relevant NHS and non-NHS resource use to be collected alongside the main trial 6) To identify the relevant items to populate the Cost and Consequences framework 7) To perform preliminary analysis of pattern of missing data Main study: CHRONOS A: To evaluate cancer control rates of focal therapy compared to stan
    Protection of trial subjects
    The study had a joint role of a Global Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) to provide overall supervision of the trials and ensure that it is being conducted in accordance with the principles of Good Clinical Practice (GCP) and the relevant regulations. The Global TSC/DMC would also safeguard the interests of trial participants, to ensure that the rights, safety and well-being of the trial participants were the most important consideration and would prevail over other interests. The TSC/DMC responsibilities also included monitoring the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2019
    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: 100
    Worldwide total number of subjects
    100
    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)
    100
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Study results are based on the Feasibility/pilot CHRONOS-A 60 patients over 12-months CHRONOS-B 60 patients over 12-months (These participants will form part of the main study if feasibility is met and funding obtained for Main Phase)

    Pre-assignment
    Screening details
    		 Inclusion: PSA </=20ng/ml , Diagnostic pre-biopsy MRI, Proven prostate adenocarcinoma, Overall Gleason score of 7, Age > 18 years, Fit to undergo all procedures Exclusion: LHRH agonist or LHRH antagonist or anti-androgen use Chronos B, Previous treatment for prostate cancer, Life expectancy less than 10 years, Unable to give informed consent

    Period 1
    Period 1 title
    IP4-CHRONOS Pilot Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CHRONOS-A Arm1 - Radical therapy
    Arm description
    		 Radical therapy (prostatectomy or radiotherapy [external beam or brachytherapy]). The type of radical therapy will be determined by physician or patient preference.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 CHRONOS-A Arm 2 Focal Therapy
    Arm description
    		 Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy or other validated energy modality as per physician/patient decision/choice.
    Arm type
    		 Focal therapy alone

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 CHRONOS-B Arm 1 Focal Therapy
    Arm description
    		 Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy or other validated energy modality as per physician and centre choice).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 CHRONOS-B Arm 2 Focal + Finasteride
    Arm description
    		 Neoadjuvant finasteride 5mg once daily for a minimum of 12 weeks (84 days) followed by focal therapy (as per control arm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    finasteride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    neoadjuvant finasteride 5mg once daily for a minimum of 12 weeks (84 days) followed by focal therapy (as per control arm).

    Arm title
    		 CHRONOS-B Arm 3 Focal + Bicalutamide
    Arm description
    		 Neoadjuvant bicalutamide 50mg once daily therapy for 12 weeks (84 days) followed by focal therapy (as per control arm).
    Arm type
    		 Experimental

    Investigational medicinal product name
    bicalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neoadjuvant bicalutamide 50mg once daily therapy for 12 weeks (84 days) followed by focal therapy (as per control arm).

    Number of subjects in period 1
    		CHRONOS-A Arm1 - Radical therapy CHRONOS-A Arm 2 Focal Therapy CHRONOS-B Arm 1 Focal Therapy CHRONOS-B Arm 2 Focal + Finasteride CHRONOS-B Arm 3 Focal + Bicalutamide
    Started
    18
    18
    22
    21
    21
    Completed
    18
    15
    21
    21
    21
    Not completed
    0
    3
    1
    0
    0
         Consent withdrawn by subject
    -
    3
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CHRONOS-A Arm1 - Radical therapy
    Reporting group description
    		 Radical therapy (prostatectomy or radiotherapy [external beam or brachytherapy]). The type of radical therapy will be determined by physician or patient preference.

    Reporting group title
    CHRONOS-A Arm 2 Focal Therapy
    Reporting group description
    		 Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy or other validated energy modality as per physician/patient decision/choice.

    Reporting group title
    CHRONOS-B Arm 1 Focal Therapy
    Reporting group description
    		 Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy or other validated energy modality as per physician and centre choice).

    Reporting group title
    CHRONOS-B Arm 2 Focal + Finasteride
    Reporting group description
    		 Neoadjuvant finasteride 5mg once daily for a minimum of 12 weeks (84 days) followed by focal therapy (as per control arm).

    Reporting group title
    CHRONOS-B Arm 3 Focal + Bicalutamide
    Reporting group description
    		 Neoadjuvant bicalutamide 50mg once daily therapy for 12 weeks (84 days) followed by focal therapy (as per control arm).

    Reporting group values
    		 CHRONOS-A Arm1 - Radical therapy CHRONOS-A Arm 2 Focal Therapy CHRONOS-B Arm 1 Focal Therapy CHRONOS-B Arm 2 Focal + Finasteride CHRONOS-B Arm 3 Focal + Bicalutamide Total
    Number of subjects
    		 18 18 22 21 21 100
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        log mean (standard deviation)
    		 68.78 ( 7.64 ) 69.28 ( 4.60 ) 64.55 ( 7.00 ) 65.71 ( 6.80 ) 66.52 ( 7.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0
        Male
    		 18 18 22 21 21 100
    Ethnicity – n (%)
    Ethnicity – n (%)
    Units: Subjects
        White
    		 8 13 14 15 17 67
        Mixed
    		 0 0 1 0 0 1
        Asian
    		 1 0 0 0 1 2
        Black
    		 0 0 1 1 1 3
        Other
    		 1 0 1 0 0 2
        Not Reported
    		 8 5 5 5 2 25
    IMD Decile – n (%)
    Units: Subjects
        Decile 1
    		 0 0 0 0 2 2
        Decile 2
    		 0 1 2 1 0 4
        Decile 3
    		 1 1 1 1 0 4
        Decile 4
    		 2 1 4 6 3 16
        Decile 5
    		 2 2 4 4 3 15
        Decile 6
    		 2 2 3 0 1 8
        Decile 7
    		 2 4 1 3 2 12
        Decile 8
    		 3 4 2 3 4 16
        Decile 9
    		 3 1 4 2 2 12
        Decile 10
    		 3 2 1 1 4 11
    Digital Rectal Examination – n (%)
    Units: Subjects
        Normal findings
    		 3 5 4 3 6 21
        Abnormal findings
    		 3 4 3 4 2 16
        No
    		 12 8 15 14 13 62
        Missing from eCRF
    		 0 1 0 0 0 1
    Current medications
    Units: Subjects
        Yes
    		 11 12 13 12 15 63
        No
    		 5 3 9 9 6 32
        Missing from eCRF
    		 2 3 0 0 0 5
    5 alpha-reductase inhibitor2
    Units: Subjects
        Yes over (or equal to) 6 months ago
    		 0 0 0 0 1 1
        Yes within 6 months
    		 0 1 0 0 0 1
        No
    		 16 14 22 21 20 93
        Missing from eCRF
    		 2 3 0 0 0 5
    Tumour grade
    Units: Subjects
        Gleason 3+3
    		 1 1 2 0 2 6
        Gleason 3+4
    		 14 13 16 17 16 76
        Gleason 4+3
    		 3 4 4 4 3 18
    Local stage
    Units: Subjects
        Clinical T2/Radiological stage <T3a
    		 18 18 20 18 19 93
        Radiological T3a
    		 0 0 2 3 2 7
    Previous or current 5ARI use?
    Units: Subjects
        Yes
    		 0 1 0 0 0 1
        No
    		 18 17 22 21 21 99
    Subject analysis sets

    Subject analysis set title
    CHRONOS-A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who took part in CHRONOS-A

    Subject analysis set title
    CHRONOS-B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who took part in CHRONOS-B

    Subject analysis sets values
    		 CHRONOS-A CHRONOS-B
    Number of subjects
    37
    64
    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)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        log mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    37
    64
    Ethnicity – n (%)
    Ethnicity – n (%)
    Units: Subjects
        White
    21
    46
        Mixed
    0
    1
        Asian
    1
    1
        Black
    0
    3
        Other
    1
    1
        Not Reported
    13
    12
    IMD Decile – n (%)
    Units: Subjects
        Decile 1
    0
    2
        Decile 2
    1
    3
        Decile 3
    2
    2
        Decile 4
    3
    13
        Decile 5
    4
    11
        Decile 6
    4
    4
        Decile 7
    6
    6
        Decile 8
    7
    9
        Decile 9
    4
    8
        Decile 10
    5
    6
    Digital Rectal Examination – n (%)
    Units: Subjects
        Normal findings
    8
    13
        Abnormal findings
    7
    9
        No
    20
    42
        Missing from eCRF
    1
    0
    Current medications
    Units: Subjects
        Yes
    23
    40
        No
    8
    24
        Missing from eCRF
    5
    0
    5 alpha-reductase inhibitor2
    Units: Subjects
        Yes over (or equal to) 6 months ago
    0
    1
        Yes within 6 months
    1
    0
        No
    30
    63
        Missing from eCRF
    5
    0
    Tumour grade
    Units: Subjects
        Gleason 3+3
    2
    4
        Gleason 3+4
    27
    49
        Gleason 4+3
    7
    11
    Local stage
    Units: Subjects
        Clinical T2/Radiological stage <T3a
    36
    57
        Radiological T3a
    0
    7
    Previous or current 5ARI use?
    Units: Subjects
        Yes
    1
    0
        No
    35
    64

    End points

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    End points reporting groups
    Reporting group title
    CHRONOS-A Arm1 - Radical therapy
    Reporting group description
    		 Radical therapy (prostatectomy or radiotherapy [external beam or brachytherapy]). The type of radical therapy will be determined by physician or patient preference.

    Reporting group title
    CHRONOS-A Arm 2 Focal Therapy
    Reporting group description
    		 Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy or other validated energy modality as per physician/patient decision/choice.

    Reporting group title
    CHRONOS-B Arm 1 Focal Therapy
    Reporting group description
    		 Focal therapy alone (high intensity focused ultrasound [HIFU] or cryotherapy or other validated energy modality as per physician and centre choice).

    Reporting group title
    CHRONOS-B Arm 2 Focal + Finasteride
    Reporting group description
    		 Neoadjuvant finasteride 5mg once daily for a minimum of 12 weeks (84 days) followed by focal therapy (as per control arm).

    Reporting group title
    CHRONOS-B Arm 3 Focal + Bicalutamide
    Reporting group description
    		 Neoadjuvant bicalutamide 50mg once daily therapy for 12 weeks (84 days) followed by focal therapy (as per control arm).

    Subject analysis set title
    CHRONOS-A
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who took part in CHRONOS-A

    Subject analysis set title
    CHRONOS-B
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who took part in CHRONOS-B

    Primary: Mean number of patients recruited per month per centre

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    End point title
    		 Mean number of patients recruited per month per centre [1]
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    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: The Study was a Pilot, therefore there was no statistical analysis as the objectives were to determine patient acceptance to the Study and randomisation arms.
    End point values
    		 CHRONOS-A CHRONOS-B
    Number of subjects analysed
    Units: Number of Subjects
        Charing Cross Hospital
    4
    32
        University Hospital Southampton NHS Foundation Tru
    19
    22
        Sunderland Royal Hospital
    4
    2
        Ashford & St Peter’s Hospitals (ASPH) NHS Foundati
    0
    6
        Royal Marsden Hospital NHS Foundation Trust
    2
    0
        Hampshire Hospital NHS Foundation Trust
    1
    0
        Kingston Hospital NHS Foundation Trust
    0
    1
        West Middlesex University Hospital
    5
    1
        The Newcastle Upon Tyne Hospitals NHS Foundation T
    2
    0
        King's College Hospital NHS Foundation Trust
    0
    0
    No statistical analyses for this end point

    Primary: Mean number of patients randomised per month per centre

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    End point title
    		 Mean number of patients randomised per month per centre [2]
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    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: The Study was a Pilot, therefore there was no statistical analysis as the objectives were to determine patient acceptance to randomisation, measured using rates of accrual and compliance, to CHRONOS-A & CHRONOS-B
    End point values
    		 CHRONOS-A CHRONOS-B
    Number of subjects analysed
    36
    64
    Units: Number of Subjects
        Charing Cross Hospital
    4
    32
        University Hospital Southampton NHS Foundation Tru
    19
    22
        Sunderland Royal Hospital
    4
    2
        Ashford & St Peter’s Hospitals (ASPH) NHS Foundati
    0
    6
        Royal Marsden Hospital NHS Foundation Trust
    2
    0
        Hampshire Hospital NHS Foundation Trust
    1
    0
        Kingston Hospital NHS Foundation Trust
    0
    1
        West Middlesex University Hospital
    5
    1
        The Newcastle Upon Tyne Hospitals NHS Foundation T
    1
    0
        King's College Hospital NHS Foundation Trust
    0
    0
    No statistical analyses for this end point

    Primary: Recruitment rate

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    End point title
    		 Recruitment rate [3]
    End point description
    Number of Subjects recruited (consented) over total number of Subjects approached
    End point type
    Primary
    End point timeframe
    12 months
    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: The Study was a Pilot, therefore there was no statistical analysis as the objectives were to determine patient acceptance to randomisation, measured using rates of accrual and compliance, to CHRONOS-A & CHRONOS-B
    End point values
    		 CHRONOS-A CHRONOS-B
    Number of subjects analysed
    211
    37
    Units: Percentage of Subjects
        number (confidence interval 95%)
    17.5 (12.7 to 23.4)
    43.2 (35.1 to 51.6)
    No statistical analyses for this end point

    Primary: Randomisation rates

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    End point title
    		 Randomisation rates [4]
    End point description
    The number of randomised patients over total number of patients recruited (consented)
    End point type
    Primary
    End point timeframe
    12 months
    Notes
    [4] - 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: The Study was a Pilot, therefore there was no statistical analysis as the objectives were to determine patient acceptance to randomisation, measured using rates of accrual and compliance, to CHRONOS-A & CHRONOS-B
    End point values
    		 CHRONOS-A CHRONOS-B
    Number of subjects analysed
    36 [5]
    64
    Units: Percentage of Subjects
        number (confidence interval 95%)
    97.3 (85.8 to 99.9)
    100 (94.4 to 100)
    Notes
    [5] - 1 patient withdrew
    No statistical analyses for this end point

    Primary: Treatment compliance

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    End point title
    		 Treatment compliance [6]
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    Notes
    [6] - 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: The Study was a Pilot, therefore there was no statistical analysis as the objectives were to determine patient acceptance to randomisation, measured using rates of accrual and compliance, to CHRONOS-A & CHRONOS-B
    End point values
    		 CHRONOS-A Arm1 - Radical therapy CHRONOS-A Arm 2 Focal Therapy CHRONOS-B Arm 1 Focal Therapy CHRONOS-B Arm 2 Focal + Finasteride CHRONOS-B Arm 3 Focal + Bicalutamide
    Number of subjects analysed
    18
    18
    22
    21
    21
    Units: Participants
    number (not applicable)
        Underwent treatment
    13
    16
    22
    21
    21
        Withdrawal
    4
    0
    0
    0
    0
        Screening failure
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    15 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    CHRONOS-A
    Reporting group description
    		 All subjects

    Reporting group title
    CHRONOS-B
    Reporting group description
    		 -

    Serious adverse events
    		 CHRONOS-A CHRONOS-B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 36 (5.56%)
    6 / 64 (9.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Pleuritic chest pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsades de Pointes
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Iatrogenic scrotal oedema (Primary)
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Urinary retention
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraphimosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urosepsis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visible haematuria
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    common bile duct stones
    Additional description: caused infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial Cellulitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: Found to have E. coli in urine microbiology and blood cultures which caused the abdominal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CHRONOS-A CHRONOS-B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 36 (22.22%)
    40 / 64 (62.50%)
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    Pleuritic Chest Pain - Bilateral pulmonary emboli on CT imaging
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    stroke
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Torsades de Pointes
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    pancytopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Dry ongoing cough, Chest xray clear
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Knee Replacement
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Painful nipples
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nausea and Vomiting
    Additional description: Reaction to Ciprofloxacin
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Worsening night sweats
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergic reaction to excipient
    Additional description: Allergic reaction to Penicillin
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Post traumatic stress disorder
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Short term memory loss
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Blood from urethral meatus when straining
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Dry Orgasm
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Ejaculatory dysfunction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Elective (planned) parathyroidectomy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Epididymo-orchitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Erectile Dysfunction
         subjects affected / exposed
    0 / 36 (0.00%)
    15 / 64 (23.44%)
         occurrences all number
    0
    15
    Failed removal of common bile duct stones
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 64 (3.13%)
         occurrences all number
    1
    2
    Haematospermia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Iatrogenic Scrotal Oedema
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Low urinary flow rate
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Lower Urinary Tract Symptoms
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    4
    Painless swelling and mild bruising of scrotal and penile skin
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Paraphimosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    patient required TURP after urosepsis and retention
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Penile numbness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Penile tip pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Prostate Inflammation
    Additional description: Post HIFU Prostate Inflammation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Prostatitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Rectal fissure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Removal of stones from common bile duct
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Severe LUTS
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Suspected common bile duct stone/pancreatitis,
    Additional description: serum amylase raised
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Sweaty testicles
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Swollen testicles
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Urgency of micturition
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Urinary Retention
         subjects affected / exposed
    1 / 36 (2.78%)
    5 / 64 (7.81%)
         occurrences all number
    1
    5
    Urine leaking around catheter
    Additional description: catheter blocked, requires flushing.
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Visible haematuria
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Infections and infestations
    Bacterial Cellulitis and Related Conditions
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Campylobacter
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Chest infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Complications of urinary catheter
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Infection following tooth extraction
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
    12 / 64 (18.75%)
         occurrences all number
    1
    12
    UTI, epididymo-orchitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2019
    Strata update as with the current number of strata, as a combination, would lead to small groups of patients in certain categories, that would not be able be used for useful analysis. • Removal or repeating sections in the trial summary boxes • One inclusion criterion has been moved to the treatment arm paragraph as it was not an inclusion criterion but rather a prompt. • Mention of partial postcode has been updated to postcode as this will be required to calculate the Index of Deprivation. • Mention of expected SAEs included within the Protocol for clarification
    11 Nov 2019
    The following changes included: • Radiation risk calculations in the IRAS form (Part B, section3 A1) • Discussion regarding standard of care scans (Part A, A22) • Addition of standard of care scans and treatment option of brachytherapy (Part A, A19) • Maximum radiation dose of patients enrolled into CHRONOS (Part B, A2) • Radiation dose for individual investigations and treatments (Part B, B1) • Additional information regarding total dose of radiation treatment (Part C, C1) • Change in MPE (Part C, C3) • Change in CRE (Part D, D4) • CHRONOS A &B PIS includes information regarding radiation risks • CHRONOS A & B ICFs reflect new version of PIS • Addition of companion PIS and ICF for optional audio-recording • For clarity the definition of brachytherapy biochemical failure and brachytherapy treatment failure have been outlined and the definition of treatment failure in CHRONOS A focal therapy arm has also been clarified within the Protocol.
    27 Jan 2020
    Hampshire Hospital NHS Foundation Trust – The PI has been updated from Amr Emara to Richard Hindley due to other work commitments. - Frimley Health NHS Foundation Trust : o Wexham Park Hospital – This new site has been added to the study. Jeetesh Bhardwa will be the PI. o Frimley Park Hospital - The PI has been updated from Jeetesh Bhardwa to the new principle investigator Simon Bott
    03 Mar 2020
    addition of a new site to the Study: - Chelsea & Westminster NHS Foundation Trust – The PI will be Mathias Winkler
    05 Nov 2020
    Addition of the site King's College Hospital NHS Foundation Trust. The PI will be Professor Gordon Muir. Removal of reference to contact the Study Clinical Manager Dr Deepika Reddy in the following PIS documents due to change of staff arrangements.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Mar 2020
    COVID-19 arose, whereby the UK was placed in lockdown and many sites were either paused for a short while or treatment times were delayed.
    -

    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/32302790
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