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    Clinical Trial Results:
    PROVENT: A randomised, double blind, placebo controlled feasibility study to examine the clinical effectiveness of aspirin and/or Vitamin D3 to prevent disease progression in men on active surveillance for prostate cancer

    Summary
    EudraCT number
    		 2014-001784-13
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2020
    First version publication date
    16 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ISRCTN91422391
    Additional study identifiers
    ISRCTN number
    		 ISRCTN91422391
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Trial CI - Mr. Greg Shaw, Centre for Cancer Prevention, QMUL. , +44 (0)20 3594 267, gregshaw@nhs.net
    Scientific contact
    Trial CI - Mr. Greg Shaw, Centre for Cancer Prevention, QMUL. , +44 (0)20 3594 267, gregshaw@nhs.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
    31 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal research objective for this study is to demonstrate the acceptability and feasibility of recruiting to a randomised chemoprevention study of standard (300mg) or low dose (100mg) aspirin vs. placebo and/or Vitamin D3 vs. placebo in patients enrolled on an active surveillance programme for prostate cancer.
    Protection of trial subjects
    Helicobacter pylori (H. pylori) has been shown to be a causative factor in GI bleeding, so all participants were tested for this at randomisation as a precaution. Patients were allowed to start their study medication, including aspirin/placebo aspirin, prior to obtaining the result of this test, as patients are not normally tested for this infection before commencing aspirin therapy and the maximum aspirin dose in this study is very low. Patients who tested positive were prescribed a course of proton pump inhibitors (PPIs) and antibiotics if they wished to continue on the study. GPs were informed. Once treated, there was no requirement to retest for this infection (as per NICE guidelines). As a precaution, patients are advised to stop the aspirin/placebo tablets 7 days prior to prostate biopsy, or any other planned surgery. Patients will be reminded about this in the clinic, and this information is also included in the PIS and Diary Cards. There is no need to stop the Vitamin D3/placebo IMP prior to surgery. Serum calcium levels will be checked at baseline and 6 monthly intervals. Administration of the Vitamin D3/placebo may be delayed if a participant experiences symptoms of hypercalcaemia. Dyspepsia has been shown to be a risk factor for NSAID GI bleeding Therefore, should new dyspeptic symptoms arise, or a gastrointestinal bleed occur (melaena, haematemesis, decreased haemoglobin) during the course of the study, then treatment with aspirin/aspirin placebo should cease immediately and permanently, and the patient will withdraw from the study. In addition, administration of IMP will be discontinued if the patient develops a condition requiring treatment with a prohibited concomitant therapy, a condition which, in the judgement of the investigator, adversely affects the participant's safety, compliance or ability to complete evaluations and/or If the investigator concludes that this course of action is in the participant's best interests.
    Background therapy
    		 N/A
    Evidence for comparator
    		 Aspirin is a common Non-Steroidal Anti-Inflammatory Drugs (NSAID) used for analgesia & as an antipyretic. These drugs inhibit the enzyme cyclo-oxygenase which is involved in the metabolism of prostaglandins & thromboxanes, which in turn are involved in many physiological pathways including inflammation & platelet function. Aspirin is a reversible inhibitor of cyclo-oxygenase 1 (COX-1). Data suggests that in contrast to other NSAIDS, it may have anti-carcinogenic properties for many cancer types, including prostate cancer. Kashiwaqi demonstrated that aspirin down-regulated the androgen receptor which drives prostate cancer metabolism, & down-regulates prostate specific antigen (PSA) levels within prostate cancer cells. Kashiwaqi demonstrated that aspirin up-regulates prostaglandin receptor subtype EP3, which again influences androgen receptor expression & cell proliferation, thought to be important in prostate carcinogenesis. Epidemiological studies have also provided data on the benefit of aspirin on prostate cancer incidence & progression. Vitamin D is a fat-soluble secosteroid responsible for intestinal absorption of calcium & phosphate. Data suggest Vitamin D may influence the incidence of cancer. The mechanism for action may be due to calcitriol’s influence on cellular proliferation, differentiation and apoptosis. The Vitamin D receptor is known to be highly expressed in epithelial cells at risk of carcinogenesis, such as prostate. Mondul identified that genetic variants related to lower 25(OH)D levels were associated with a decreased risk of aggressive prostate cancer. it has been suggested that Vitamin D deficiency over time may contribute to the progression of insignificant prostate cancer to clinically significant disease. Marshall & colleagues evaluated Vitamin D supplementation in men with low to intermediate risk prostate cancer, reporting that those receiving Vitamin D had a lower number of positive cancer cores on repeat biopsy at 1 year.
    Actual start date of recruitment
    16 Dec 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: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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)
    64
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment will take place in prostate clinics at 6 participating centres, based within the UK only. The aim will be to recruit 102 participants over a 12 month period, starting Dec 2016. Recruitment tools = study invitation letter, trial poster & a trial website.

    Pre-assignment
    Screening details
    		 Potentially eligible patient given a Patient Info Sheet & added to local Pre-screening log, (initials & DOB only). Informed consent taken from interested patients & pre-randomisation Eligibility Assessment conducted. Participants must have a corrected serum calcium level ≤ 2.65mmol/l & a negative H Pylori test result prior to starting IMP.

    Period 1
    Period 1 title
    Overall Trial Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Randomisation will be by bespoke web-based application. All relevant research staff will be trained in its use. Eligible participants will be randomised in a 6-arm 1:1:1:1:1:1 design. Randomised blocks will be used to maintain balance amongst these 6 arms, & the aspirin placebo groups will be block randomised to either small or large aspirin placebo tablets. The allocated unique study number will correspond to a particular arm of the trial, & used to label & identify all trial samples.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Large Aspirin (Active) & Vitamin D (Active)
    Arm description
    		 Aspirin 300mg & Vitamin D
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aspirin 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take 1 Aspirin tablet, whole, with water at the same time of every day, ideally in the morning. The tablets must be taken daily for 18 months. If you miss a tablet, you may take it later, as long as it is at least 6 hours before your next dose is due - do not take more than one study tablet at the same time, and no more than two per 24 hours. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat or sunlight.

    Investigational medicinal product name
    Vitamin D Oil
    Investigational medicinal product code
    Other name
    Vigantol® Oil
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Take 8 drops of Vitamin D solution with food at the same time of day, ideally in the morning. The drops will be taken daily for 18 months. The solution may be dropped onto bread, or taken on a spoon, mixed with a small quantity of fruit juice if preferred, but NOT added to a full glass of beverage. If you miss the drops, you may take them later or with the next dose. Do not take more than two days doses together. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat & sunlight.

    Arm title
    		 Large Aspirin (Active) & Vitamin D (Placebo)
    Arm description
    		 Aspirin 300mg + Vitamin D3 placebo
    Arm type
    		 Active comparator & placebo

    Investigational medicinal product name
    Vitamin D Placebo
    Investigational medicinal product code
    Other name
    Miglyol®812 Oil
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Take 8 drops of Vitamin D solution with food at the same time of day, ideally in the morning. The drops will be taken daily for 18 months. The solution may be dropped onto bread, or taken on a spoon, mixed with a small quantity of fruit juice if preferred, but NOT added to a full glass of beverage. If you miss the drops, you may take them later or with the next dose. Do not take more than two days doses together. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat & sunlight.

    Investigational medicinal product name
    Aspirin 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take 1 Aspirin tablet, whole, with water at the same time of every day, ideally in the morning. The tablets must be taken daily for 18 months. If you miss a tablet, you may take it later, as long as it is at least 6 hours before your next dose is due - do not take more than one study tablet at the same time, and no more than two per 24 hours. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat or sunlight.

    Arm title
    		 Small Aspirin (Active) & Vitamin D (Active)
    Arm description
    		 Aspirin 100mg + Vitamin D3
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aspirin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take 1 Aspirin tablet, whole, with water at the same time of every day, ideally in the morning. The tablets must be taken daily for 18 months. If you miss a tablet, you may take it later, as long as it is at least 6 hours before your next dose is due - do not take more than one study tablet at the same time, and no more than two per 24 hours. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat or sunlight.

    Investigational medicinal product name
    Vitamin D Oil
    Investigational medicinal product code
    Other name
    Vigantol® Oil
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Take 8 drops of Vitamin D solution with food at the same time of day, ideally in the morning. The drops will be taken daily for 18 months. The solution may be dropped onto bread, or taken on a spoon, mixed with a small quantity of fruit juice if preferred, but NOT added to a full glass of beverage. If you miss the drops, you may take them later or with the next dose. Do not take more than two days doses together. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat & sunlight.

    Arm title
    		 Small Aspirin (Active) & Vitamin D (Placebo)
    Arm description
    		 Aspirin 100mg + Vitamin D3 placebo
    Arm type
    		 Active comparator & placebo

    Investigational medicinal product name
    Vitamin D Oil placebo
    Investigational medicinal product code
    Other name
    Miglyol®812 Oil
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Take 8 drops of Vitamin D solution with food at the same time of day, ideally in the morning. The drops will be taken daily for 18 months. The solution may be dropped onto bread, or taken on a spoon, mixed with a small quantity of fruit juice if preferred, but NOT added to a full glass of beverage. If you miss the drops, you may take them later or with the next dose. Do not take more than two days doses together. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat & sunlight.

    Investigational medicinal product name
    Aspirin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take 1 Aspirin tablet, whole, with water at the same time of every day, ideally in the morning. The tablets must be taken daily for 18 months. If you miss a tablet, you may take it later, as long as it is at least 6 hours before your next dose is due - do not take more than one study tablet at the same time, and no more than two per 24 hours. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat or sunlight.

    Arm title
    		 Aspirin (placebo) + Vitamin D3 (active)
    Arm description
    		 Aspirin placebo + Vitamin D3
    Arm type
    		 Active comparator & placebo

    Investigational medicinal product name
    Aspirin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take 1 Aspirin tablet, whole, with water at the same time of every day, ideally in the morning. The tablets must be taken daily for 18 months. If you miss a tablet, you may take it later, as long as it is at least 6 hours before your next dose is due - do not take more than one study tablet at the same time, and no more than two per 24 hours. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat or sunlight.

    Investigational medicinal product name
    Vitamin D Oil
    Investigational medicinal product code
    Other name
    Vigantol® Oil
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Take 8 drops of Vitamin D solution with food at the same time of day, ideally in the morning. The drops will be taken daily for 18 months. The solution may be dropped onto bread, or taken on a spoon, mixed with a small quantity of fruit juice if preferred, but NOT added to a full glass of beverage. If you miss the drops, you may take them later or with the next dose. Do not take more than two days doses together. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat & sunlight.

    Arm title
    		 Aspirin (placebo) + Vitamin D3 (placebo)
    Arm description
    		 Aspirin placebo + Vitamin D3 placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Aspirin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take 1 Aspirin tablet, whole, with water at the same time of every day, ideally in the morning. The tablets must be taken daily for 18 months. If you miss a tablet, you may take it later, as long as it is at least 6 hours before your next dose is due - do not take more than one study tablet at the same time, and no more than two per 24 hours. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat or sunlight.

    Investigational medicinal product name
    Vitamin D Placebo
    Investigational medicinal product code
    Other name
    Miglyol®812 Oil
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Take 8 drops of Vitamin D solution with food at the same time of day, ideally in the morning. The drops will be taken daily for 18 months. The solution may be dropped onto bread, or taken on a spoon, mixed with a small quantity of fruit juice if preferred, but NOT added to a full glass of beverage. If you miss the drops, you may take them later or with the next dose. Do not take more than two days doses together. Otherwise, missed doses should be recorded on the diary card, plus any comments or reasons for the missed dose. If you vomit after taking a dose of your study medication, do not take a further dose that day, but record this on your diary card. If this happens again and you think it may be related to the medication, then please contact your local research team. Please store your medicines in a cool, dry place, away from heat & sunlight.

    Number of subjects in period 1
    		Large Aspirin (Active) & Vitamin D (Active) Large Aspirin (Active) & Vitamin D (Placebo) Small Aspirin (Active) & Vitamin D (Active) Small Aspirin (Active) & Vitamin D (Placebo) Aspirin (placebo) + Vitamin D3 (active) Aspirin (placebo) + Vitamin D3 (placebo)
    Started
    17
    16
    19
    18
    16
    18
    Completed
    7
    10
    8
    9
    10
    9
    Not completed
    10
    6
    11
    9
    6
    9
         Adverse event, serious fatal
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    1
    -
    1
    1
    1
    -
         Physician decision
    5
    2
    6
    3
    3
    1
         Inter-current illness
    -
    -
    1
    -
    -
    -
         Testicular pain
    -
    -
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    1
    -
    -
    1
         Patient excluded
    2
    2
    1
    2
    1
    1
         Patient unhappy to continue
    -
    -
    -
    -
    -
    1
         Lost to follow-up
    -
    1
    -
    1
    -
    1
         Patient wishes to come off Active Surveillance
    2
    -
    1
    1
    1
    3
         Unacceptable toxicity/intolerable side effects
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial Period
    Reporting group description
    		 All randomised patients.

    Reporting group values
    		 Overall Trial Period Total
    Number of subjects
    		 104 104
    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
        median (inter-quartile range (Q1-Q3))
    		 61 (56 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 104 104
    Subject analysis sets

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised into the PROVENT trial.

    Subject analysis set title
    Active Vitamin D patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those patients receiving active vitamin D3 treatment

    Subject analysis set title
    Placebo Vitamin D Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those patients receiving placebo vitamin D3 treatment

    Subject analysis set title
    Active Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those patients receiving active aspirin treatment (either 100mg OR 300mg)

    Subject analysis set title
    Placebo Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving placebo aspirin treatment

    Subject analysis set title
    100mg Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving 100mg of aspirin

    Subject analysis set title
    300mg Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving 300mg of aspirin

    Subject analysis set title
    Pathology review baseline subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eighty-two patients whose biopsy tissue was centrally-reviewed after baseline biopsy

    Subject analysis set title
    Pathology review month-12 subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Twenty-five patients whose biopsy tissue was centrally-reviewed at 12 months

    Subject analysis set title
    Paired MRI patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients that had MRI lesion detected at baseline and 12 months for volume comparison

    Subject analysis sets values
    		 All patients Active Vitamin D patients Placebo Vitamin D Patients Active Aspirin Patients Placebo Aspirin Patients 100mg Aspirin Patients 300mg Aspirin Patients Pathology review baseline subjects Pathology review month-12 subjects Paired MRI patients
    Number of subjects
    104
    52
    52
    70
    34
    37
    33
    82
    25
    11
    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
        median (inter-quartile range (Q1-Q3))
    61 (56 to 66)
    62 (56 to 67)
    61 (56 to 67)
    61 (56 to 66)
    65 (56 to 67)
    62 (59 to 66)
    60 (55 to 64)
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    104

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Large Aspirin (Active) & Vitamin D (Active)
    Reporting group description
    		 Aspirin 300mg & Vitamin D

    Reporting group title
    Large Aspirin (Active) & Vitamin D (Placebo)
    Reporting group description
    		 Aspirin 300mg + Vitamin D3 placebo

    Reporting group title
    Small Aspirin (Active) & Vitamin D (Active)
    Reporting group description
    		 Aspirin 100mg + Vitamin D3

    Reporting group title
    Small Aspirin (Active) & Vitamin D (Placebo)
    Reporting group description
    		 Aspirin 100mg + Vitamin D3 placebo

    Reporting group title
    Aspirin (placebo) + Vitamin D3 (active)
    Reporting group description
    		 Aspirin placebo + Vitamin D3

    Reporting group title
    Aspirin (placebo) + Vitamin D3 (placebo)
    Reporting group description
    		 Aspirin placebo + Vitamin D3 placebo

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised into the PROVENT trial.

    Subject analysis set title
    Active Vitamin D patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those patients receiving active vitamin D3 treatment

    Subject analysis set title
    Placebo Vitamin D Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those patients receiving placebo vitamin D3 treatment

    Subject analysis set title
    Active Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those patients receiving active aspirin treatment (either 100mg OR 300mg)

    Subject analysis set title
    Placebo Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving placebo aspirin treatment

    Subject analysis set title
    100mg Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving 100mg of aspirin

    Subject analysis set title
    300mg Aspirin Patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients receiving 300mg of aspirin

    Subject analysis set title
    Pathology review baseline subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eighty-two patients whose biopsy tissue was centrally-reviewed after baseline biopsy

    Subject analysis set title
    Pathology review month-12 subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Twenty-five patients whose biopsy tissue was centrally-reviewed at 12 months

    Subject analysis set title
    Paired MRI patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients that had MRI lesion detected at baseline and 12 months for volume comparison

    Primary: Patient recruitment

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    End point title
    		 Patient recruitment [1]
    End point description
    There is no formal analysis for patient recruitment. A target of 102 patients (approximately 17 per arm) was set and met.
    End point type
    Primary
    End point timeframe
    December 2016 to December 2017
    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: There was no formal statistical analysis of the primary endpoint. There was an aim to recruit 102 patients based on an estimated 30% recruitment rate. The number of patients actually recruited was 104 and so the primary endpoint was met.
    End point values
    		 All patients
    Number of subjects analysed
    104 [2]
    Units: Patients recruited
    104
    Notes
    [2] - No formal analysis for patient recruitment. A target of 102 patients (approximately 17 per arm) was
    No statistical analyses for this end point

    Secondary: Disease progression by MRI

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    End point title
    		 Disease progression by MRI
    End point description
    Disease progression is defined as increase in lesion volume of >33% or an upgrading of MRI stage of disease to T3 or above. In the case where no lesion was identified by MRI screening, disease progression is defined as the development of a lesion of 0.2cc or greater and being assigned a PIRADS score of 4 or 5 Disease regression is defined as a decrease in lesion volume of > 33% or the absence of a lesion at 12 months where one was detected at baseline
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Large Aspirin (Active) & Vitamin D (Active) Large Aspirin (Active) & Vitamin D (Placebo) Small Aspirin (Active) & Vitamin D (Active) Small Aspirin (Active) & Vitamin D (Placebo) Aspirin (placebo) + Vitamin D3 (active) Aspirin (placebo) + Vitamin D3 (placebo) Active Vitamin D patients Placebo Vitamin D Patients Active Aspirin Patients Placebo Aspirin Patients 100mg Aspirin Patients 300mg Aspirin Patients
    Number of subjects analysed
    9
    8
    8
    5
    9
    8
    26
    21
    30
    17
    13
    33
    Units: Patients
        Disease regression
    1
    5
    5
    0
    3
    2
    9
    7
    11
    5
    5
    6
        Stable disease
    4
    3
    2
    4
    6
    6
    12
    13
    13
    12
    6
    7
        Disease progression
    4
    0
    1
    1
    0
    0
    5
    1
    6
    0
    2
    4
    No statistical analyses for this end point

    Secondary: Biochemical disease progression (PSA)

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    End point title
    		 Biochemical disease progression (PSA)
    End point description
    Biochemical disease progression was defined as observing an increase in PSA levels of at least 50% over 12 months. Biochemical disease regression was defined as observing a decrease in PSA levels of at least 50% over 12 months.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Large Aspirin (Active) & Vitamin D (Active) Large Aspirin (Active) & Vitamin D (Placebo) Small Aspirin (Active) & Vitamin D (Active) Small Aspirin (Active) & Vitamin D (Placebo) Aspirin (placebo) + Vitamin D3 (active) Aspirin (placebo) + Vitamin D3 (placebo) Active Vitamin D patients Placebo Vitamin D Patients Active Aspirin Patients Placebo Aspirin Patients 100mg Aspirin Patients 300mg Aspirin Patients
    Number of subjects analysed
    12
    13
    11
    10
    12
    15
    35
    38
    46
    27
    21
    25
    Units: Patients
        Disease Regression
    1
    2
    0
    0
    0
    1
    1
    3
    3
    1
    0
    3
        Stable Disease
    9
    10
    10
    10
    10
    13
    29
    33
    39
    23
    20
    19
        Disease Progression
    2
    1
    11
    0
    2
    1
    5
    2
    4
    3
    1
    3
    No statistical analyses for this end point

    Secondary: Histological disease progression by Gleason scoring

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    End point title
    		 Histological disease progression by Gleason scoring
    End point description
    Histological disease progression is defined as an increase in Gleason score or primary grade upon repeat biopsy at 12 months Histological disease regression is defined as a decrease in Gleason score or primary grade upon repeat biopsy at 12 months
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Large Aspirin (Active) & Vitamin D (Active) Large Aspirin (Active) & Vitamin D (Placebo) Small Aspirin (Active) & Vitamin D (Active) Small Aspirin (Active) & Vitamin D (Placebo) Aspirin (placebo) + Vitamin D3 (active) Aspirin (placebo) + Vitamin D3 (placebo) Active Vitamin D patients Placebo Vitamin D Patients Active Aspirin Patients Placebo Aspirin Patients 100mg Aspirin Patients 300mg Aspirin Patients
    Number of subjects analysed
    5
    8
    8
    5
    8
    9
    21
    22
    26
    17
    13
    13
    Units: Patients
        Disease Regression
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    1
    0
        Stable Disease
    4
    4
    4
    3
    5
    8
    13
    15
    15
    13
    7
    8
        Disease Progression
    1
    4
    3
    2
    3
    1
    7
    7
    10
    4
    5
    5
    No statistical analyses for this end point

    Secondary: Histological disease progression by Maximum Cancer Core Length

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    End point title
    		 Histological disease progression by Maximum Cancer Core Length
    End point description
    Disease progression will be defined as a 50% increase in maximum cancer core length as determined by repeat biopsy at 12 months Disease regression will be defined as a 50% decrease in maximum cancer core length as determined by repeat biopsy at 12 months
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Large Aspirin (Active) & Vitamin D (Active) Large Aspirin (Active) & Vitamin D (Placebo) Small Aspirin (Active) & Vitamin D (Active) Small Aspirin (Active) & Vitamin D (Placebo) Aspirin (placebo) + Vitamin D3 (active) Aspirin (placebo) + Vitamin D3 (placebo) Active Vitamin D patients Placebo Vitamin D Patients Active Aspirin Patients Placebo Aspirin Patients 100mg Aspirin Patients 300mg Aspirin Patients
    Number of subjects analysed
    5
    8
    8
    5
    8
    9
    21
    22
    26
    17
    13
    13
    Units: Patients
        Disease Regression
    1
    0
    1
    0
    2
    0
    4
    0
    2
    2
    1
    1
        Stable Disease
    3
    2
    5
    3
    3
    3
    11
    8
    13
    6
    8
    5
        Disease Progression
    1
    6
    2
    2
    3
    6
    6
    14
    11
    9
    4
    7
    No statistical analyses for this end point

    Secondary: Pathology review (baseline)

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    End point title
    		 Pathology review (baseline)
    End point description
    Central review of biopsy tissue for 82 patients at baseline
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Pathology review baseline subjects
    Number of subjects analysed
    82
    Units: Concordant pathology reports
        Concordant reviews
    77
        Discordant Gleason score
    3
        Discordant Other
    2
    No statistical analyses for this end point

    Secondary: Pathology review at 12 months

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    End point title
    		 Pathology review at 12 months
    End point description
    Central review of biopsy tissue at 12 months
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pathology review month-12 subjects
    Number of subjects analysed
    25
    Units: Concordant pathology reports
        Concordant report
    22
        Discordant Gleason score
    0
        Discordant other
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs should be reported from the date of first randomisation until the end of trial, defined as the date of the Last Patient Last Visit (LPLV) & 30 days.
    Adverse event reporting additional description
    3 monthly fup. Adverse event CRF completed & patient diary checked by the research nurse at each appointment. Patient stops treatment early or does not attend their ‘End of Study’ appointment? The LCO is responsible for checking their AE status via a telephone at least 30 days after the date the participant has stated they stopped their IMP.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    A: Aspirin 300mg & Vitamin D
    Reporting group description
    		 -

    Reporting group title
    B: Aspirin 300mg & Vitamin D placebo
    Reporting group description
    		 -

    Reporting group title
    C: Aspirin 100mg & Vitamin D
    Reporting group description
    		 -

    Reporting group title
    D: Aspirin 100mg & Vitamin D placebo
    Reporting group description
    		 -

    Reporting group title
    E: Aspirin placebo & Vitamin D
    Reporting group description
    		 -

    Reporting group title
    F: Aspirin placebo & Vitamin D placebo
    Reporting group description
    		 -

    Serious adverse events
    		 A: Aspirin 300mg & Vitamin D B: Aspirin 300mg & Vitamin D placebo C: Aspirin 100mg & Vitamin D D: Aspirin 100mg & Vitamin D placebo E: Aspirin placebo & Vitamin D F: Aspirin placebo & Vitamin D placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 16 (12.50%)
    2 / 19 (10.53%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mass in brain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal bleeding
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention postoperative
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Febrile infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 A: Aspirin 300mg & Vitamin D B: Aspirin 300mg & Vitamin D placebo C: Aspirin 100mg & Vitamin D D: Aspirin 100mg & Vitamin D placebo E: Aspirin placebo & Vitamin D F: Aspirin placebo & Vitamin D placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 17 (29.41%)
    9 / 16 (56.25%)
    6 / 19 (31.58%)
    4 / 18 (22.22%)
    7 / 16 (43.75%)
    11 / 18 (61.11%)
    Vascular disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Abdominal aortic aneurysm
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Abdominal crampy pains
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Acid reflux
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Acute back pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Arm pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Back ache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bacterial infection due to helicobacter pylori (H. pylori)
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Bleeding postoperative
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bloating
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood in urine
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood stool
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Chest infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Coccyx pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cold
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    1
    0
    2
    3
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dark circles under eyes
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fast Heart Beat
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fever
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Flu-like symptoms
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Flu prophylaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Foot pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fractured ribs
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemospermia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hay fever
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Head cold
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hematuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Indigestion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Left hip pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Left knee meniscal tear
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Leg pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Lichen simplex
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nose bleed
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 16 (18.75%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    3
    0
    0
    0
    2
    Pain in hips, knees and shoulders
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pain stomach
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pins and needles
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Postoperative pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Prolapsing haemorrhoid
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rash, headache, insomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rectal bleeding
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Removal of basal cell
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sore throat
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 16 (12.50%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Stomach ache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Stomach acid
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Swelling (r) testicle
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Swollen toes
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upset stomach
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Urinary urgency
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urine volume increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Haematuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Post procedural constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 16 (18.75%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 18 (5.56%)
         occurrences all number
    4
    6
    0
    0
    2
    2
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye disorders
    Teary eyes
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    2
    0
    0
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Gastrooesophageal reflux disease
    Additional description: 1
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Lichen planus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Lower urinary tract symptoms
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Gout
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Infections and infestations
    Fever/Virus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2016
    Substantial Amendment #1 Changes to the protocol • New Chief Investigator. • Change in Co-investigator, additions of new Collaborators, Trial Statistician. • Updated contact details of the Project Manager. • A new Representative of the Sponsor • Removal of the MRI review process & Trial Radiologist • One additional progression event – an upgrading of MRI Disease stage to ≥3 • An increased number of Vitamin D3 drops to be ingested from 6, to 8 drops per day. This is due to a change in the bottle dropper size. The dosage remains unchanged. • Removal of the use of email/SMS to send participants appointment reminders & compliance prompts. • Non-Compliance changed to Non-Conformance with a definition. • Additional safeguards around dispensation of the study drugs. • An update on SAE reporting from the trials unit to the sponsor. • SAE reporting from the trials unit to the sponsor updated and ‘Service Level Agreement ‘replaced by the’ Conditions of Sponsorship’ • Removal of the requirement for CIOMs form completion as it's not a requirement for CTIMPS within the UK. • Clarification about PIs ability to sign SAEs and SUSARs electronically within study app. • More explicit instructions for unblinding participants in the event of a SUSAR. • Clearer definition of the reference safety information. • Administrative changes and clarified definition of source data. • Provision of urine for translational research to Myriad Genetics. Inc. This is not an additional sample. The company are receiving 15ml of the 35ml sample we are already collecting. • More information on storage of biopsy samples and storage & testing of urine samples. • Treatment holiday more explicitly defined, and a definition for lost to follow-up added. • Patients may be withdrawn from trial medication, and/or the study in the event of interruption of study drug intake for greater than 60 days.
    24 Aug 2016
    Substantial Amendment #1 continued. • Patients who interrupt study drug intake for a cumulative total of greater than 90 60 days, in a 3 month period between follow-up appointments will be considered as non-compliant and will be discontinued from the study. • Various administration changes, e.g. the ‘Withdrawal from Treatment’ CRF is now called the ‘End of Study’ CRF, unblinding patients. • Clearer ‘long-term follow-up’ &‘End of Study’ definitions. • The 'End of Study' has been redefined in the protocol. Long-term follow-up has been excluded and a post treatment pharmacovigilence period has been accommodated. • Plans for dissemination of study results to the public added. • Collection of tissue in the event of a participant undergoing a radical prostatectomy clarified. • More explicit instructions for unblinding participants in the event of a SUSAR. • Adding more precautions to safeguard patient’s safety in regards to biopsy procedure. • Information on dose interruptions. • Addition of post treatment pharmacovigilance period. End of Study Visit will take place at 18 months plus ≥ to 30 days. • Adding a new suggestion for ingesting Vitamin D3: added to a small quantity of fruit juice. • Addition of a link to the study website and addition of IRAS ID number. • Addition of new references. • Clear documentation to site staff that pregnancies do not have to be reported. • Administrative changes to treatment discontinuation. • Pre-screening log. Data not entered into trial application. Informed Consent, Eligibility Assessed & Blood Samples for PSA & Serum taken. Participants must fulfil the inclusion and exclusion criteria. All patients who meet the eligibility criteria and are randomised will be included in the intention to treat (ITT) analysis. • PID would not be used to send appointment reminders. • Purpose for collecting contact details updated.
    24 Aug 2016
    Substantial amendment #1 continued (2) Changes to sites • Number of sites increased from ‘Up to 5’, to ‘Up to 7’ to accommodate Guy's & Coventry Hospitals. Changes to study documents • PROVENT Consent Form V1.0 - Removal of consent to receive appointment reminders - Clearer documentation around the use of samples and personal details for the collection of long-term follow-up data. - Administrative changes. - Not necessary to have the study number on the consent form. - Addition of IRAS ID number. - More information on completing the consent form. • PROVENT Patient Information Sheet V2.0 - Update re: exclusive storage & testing of urine samples by QMUL - More explicit instructions for taking the Vitamin D3 oil. - Addition of information regarding the reimbursement of travel expenses. - Update re: collection & storage of participant contact details and their use to collect long-term follow-up data as part of a separate, ethically approved research study - Administrative amendments. • PROVENT Patient Diary V2.0 - Advice re: back up reference for contact details. - More explicit instructions for taking the Vitamin D3 oil. - Increase in number of drops to be taken, from 6 to 8. - New diary card & dosage instructions given out more frequently. • PROVENT IMP Labels; - PROVENT Label Aspirin 100 – Update V1.0: Change of CI and change in dispensing instructions to 'Take as directed in patient diary'. - PROVENT Label Aspirin 300 – Update V1.0: Change of CI and change in dispensing instructions to 'Take as directed in patient diary'. - PROVENT Vitamin D – Update V1.0: Change of CI and increase in number of drops from 6 to 8 and change in dispensing instructions to 'Take as directed in patient diary'. - PROVENT Outer Pack Label Aspirin 100 & Vitamin D – Update V1.0: Change of CI. - PROVENT Outer Pack Label Aspirin 100 & Vitamin D – Update V1.0: Change of CI. - PROVENT labels for replacement IMP dropped.
    05 Jun 2017
    Substantial Amendment #2. Changes to Protocol, V3.0, 5th May 2016 • Change of Chief Investigator from Professor Thomas Powles to Mr Greg Shaw, effective from the 1st June 2017. • Reduction of the randomisation period from 18 to 12 months, to accommodate the shorter expiry date on one of the I MPs, whilst still being able to offer participants the full 18 months treatment. • Removal of TMPRESS-2 ERG testing by Hologic Gen Probe as a result of financial constraints experienced by the company. • Replacement of PCA3 testing with 'exploratory research' due to Hologic Gen Probe no longer being able to provide the required collection tubes and reagents for the duration of the trial. • Revised timings of the recruitment rate review to 3, 6, 9, & 12 month, to reflect the new randomisation period. • More accurate definition of the inclusion criterion relating to Gleason grading. Some patients with Gleason Grade 3+4 prostate cancer would be eligible for active surveillance, patients with 4+3 would not by NICE and European Association of Urology guidance. • More accurate definition of the exclusion criterion relating to participation in other trials. All active surveillance patients at one of our sites are encouraged to participate in an observational/questionnaire study. The amendment will allow these patients to join PROVENT also. Addition of resources to assist sites with recruitment; a patient invitation letter, a trial poster & a study website. • Justification for the absence of an IMPD for the Aspirin placebo. • Correction to the composition details of the Vitamin D3 active product; 40 drops/lml = 20,000 IU/0.Smg cholecalciferol. Currently documented as 30 drops. • Revised timings for the baseline serum calcium blood test result. An existing serum result will be acceptable if taken within 2 months prior to the Eligibility Assessment date.
    05 Jun 2017
    Substantial Amendment #2 (continued) More explicit instructions regarding a participant's right to request that their treatment is unblinded. Removal of instructions for sending samples by ambient temperature. Sites agreed to freeze samples locally, for bulk shipment at a later date. • Addition of the Project Manager's name. • Correction to Mr Paul Cathcart's title. • Removal of CR-UK's endorsement due to the delayed start of the trial • Minor administrative amendments, e.g. , correction to the protocol version & date. Changes to sites • Removal of Bedford Hospital • The addition of 4 sites: Churchill Hospital, Oxford, Southampton General Hospital, Western General Hospital, Edinburgh and Darent Valley Hospital, Kent. Changes to study documents • PROVENT Consent Form V2.0, 22nd March 2016: - Screening/Pre-randomisation ID: One additional box added to accommodate the full PROVENT pre-randomisation ID number. - Updated with the details of the new version of the Patient Information Sheet. • PROVENT Patient Information Sheet V3.0, 5th May 2016: - Reduction of the randomisation period from 18 to 12 months, to accommodate the shorter expiry date on one of the IMPs, whilst still being able to offer participants the full 18 months treatment. - Removal of CR-UK's endorsement due to the delayed start of the trial. - Revised timings for the baseline serum calcium blood test result. An existing serum result will be acceptable if taken within 2 months prior to the Eligibility Assessment date. • PROVENT Label Aspirin 100 -Update V2.0 & PROVENT Label Aspirin 300 - Update V2.0: Combined to produce one label for both drugs, i.e. ASPIRIN 300mg OR Aspirin 100mg OR PLACEBO, for the following reasons; (a)The change to the label means all packs are fully blinded from the outer packs (b) Having single Master labels for the tablet pots & outer cartons makes the trial more secure. • PROVENT Wallet Cards: - Contact details updated
    04 Sep 2017
    Substantial amendment #3. NB: The amendment date is the date it was approved by the MREC. There was no requirement to submit to the Regulatory Authority. The purpose of the amendment was to add the Royal Free Hospital London as a Patient Identification Site for University College Hospital London. No trial documents were changed as a consequence.
    03 Oct 2018
    Substantial Amendment #4 Changes to Protocol, V4.0, 16th February 2017 • Change of sponsor representative details • Change of Project Manager from Roseann Kealy to Adedayo Oke • Change of Trial Statistician from Amar Ahmed to Jacqueline Murphy • Clarification on where study prostate tissue samples will be stored • The addition of ‘Occurrence of any other malignancy’ as a reason for early study withdrawal • The dietary supplements/medication composition description changed from “Vitamin D3” to the less specific “Vitamin D” on page 10 of the protocol. • The addition of Sarcoidosis and Tuberculosis to the protocol exclusion criteria list. • The IMP bottle /container labels were corrected in the protocol to reflect those approved & used for the study. • Clarification on the frequency of Digital Rectal Examination (DRE), and the timing of repeat MRI Scans and Prostate Biopsies which should be conducted in line with routine care. DRE and post-DRE urine sample collected at the 12 and 18 month visits only. • Removal of the communication plan between the CI/PI and members of the study team document, from the list of study documents to be filed in the Investigator Files (IF) and Pharmacy Site Files (PSF). • The reference to the study type in the protocol is corrected from Type B to Type A based on the MHRA Guidelines. • Administrative changes to the Schedule of Assessment table making it consistent with the wording within the protocol and associated SOPs/manuals which accurately reflects the study procedures & time points. • The secondary objective “50% increase in serum PSA at 12 months from baseline” revised to “Change in serum PSA at 6 and 12 months from baseline” • SAE definition updated to include “Is otherwise considered medically significant by the investigator” • Removal of "Interruption of study drug intake for greater than 60 days from the criteria for early study/IMP withdrawal. Addition to the study website: • Information added to the study
    17 Dec 2019
    Substantial Amendment #5 Changes to Protocol, V5.0, 18th August 2018 • Updated protocol number, version and date • Project Manager name and contact details updated. • A new Trial Statistician • A change to the end of trial definition to allow for the receipt of the Cell Cycle Progression (CCP (ii)) analyses results. Our principal site, with the highest number of participants has experienced some difficulty obtaining the 12 month pathology samples required for CCP analysis. The CCP scores relate to the secondary endpoint ‘To evaluate markers of disease progression’. The amendment will afford us more time for this activity. The change to the end of trial definition does not involve an extension to participants’ treatment or follow-up. • A revision of the study duration to accommodate the change in end of trial definition.

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

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