Prostate Cancer Screening Trial Using A Group of Radiological Approaches Including MRI and Ultrasound
Conditions: Prostate Neoplasm
Sponsor: Imperial College London

IP1 - PROSTAGRAM 
Protocol No: 
18HH4595  
Sponsor:  
Imperial College London  
V 1.2 01MAY2019 
 
 
IRAS: 247728               Clinical Study Protocol           
   Version 1.2 01MAY2019 
 
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CLINICAL STUDY PROTOCOL 
 
 
(ICTU Adopted) 
 
 
 
 
 
 
Full Study Title: 
PROstate Cancer Screening Trial using A Group of 
Radiological Approaches including MRI and ultrasound 
 
 
Short Study title / Acronym: 
IP1 - PROSTAGRAM 
 
 
 
Sponsor: 
 
 
 
Imperial College London 
 
 
 
Version no:                        1.2            
 
 
 
 
 
Protocol Date:  
 
17 December 2018  
 
 
 
 
Property of Imperial Clinical Trials Unit (ICTU) 
May not be used, divulged or published without the consent of ICTU 
 
This protocol has regard for the HRA guidance 
 
 
 
 
 
   
 
 

IP1 - PROSTAGRAM 
Protocol No: 
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Sponsor:  
Imperial College London  
V 1.2 01MAY2019 
 
 
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RESEARCH REFERENCE NUMBERS 
 
IRAS ID:  
247728  
REC Reference Number: 
118/LO/1338  
ISRCTN Number / Clinical trials.gov 
Number: 
ISRCTN43502108 / NCT03702439 
 
 
Sponsor Protocol Number:  
18HH4595 
Funder reference: 
Wellcome Trust: 204998/Z/16/Z 
Urology Foundation: 180426  
 
 
 
Keywords: 
 
prostate cancer, screening, prostate imaging, non-contrast MRI, PSA, prostate biopsy  
 
 
 
 

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Protocol No: 
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Sponsor:  
Imperial College London  
V 1.2 01MAY2019 
 
 
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CONTACT LIST 
 
Chief Investigator  
 
Professor Hashim Uddin Ahmed 
Imperial College London 
5L28, Laboratory Block, Charing Cross Campus 
London 
W6 8RP 
 
Email: hashim.ahmed@imperial.ac.uk 
Tel: 
020 7589 5111 
 
 
 
Sponsor 
 
Becky Ward, Research Governance Manager 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building, Norfolk Place, London, W2 1PG 
Tel: 0207 594 9459 | E-mail: becky.ward@imperial.ac.uk 
http://www.imperial.ac.uk/joint-research-compliance-office   
 
 
 
Funder 
 
Wellcome Trust 
Gibbs Building 
215 Euston Road 
London NW1 2BE 
UK 
 
 
The Urology Foundation  
1-2 St Andrew’s Hill, London  
EC4V 5BY  
UK  
 
 
 
 
 

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Sponsor:  
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Co-Investigators 
 
Mr David Eldred-Evans 
Clinical Research Fellow and Specialist Registrar in Urology 
5L01 Laboratory Block, Charing Cross Campus, Imperial College London  
W6 8RP 
Telephone: 0203 311 5473 
Email: d.eldred-evans@imperial.ac.uk  
 
Mr Mathias Winkler 
Imperial College Healthcare NHS Trust 
Department of Urology, Charing Cross Hospital, Fulham Palace Road, London 
W6 8RF 
Telephone: 020 3311 1234 
Email: mathias.winkler@nhs.net  
 
Dr Henry Tam 
Imperial College Healthcare NHS Trust 
Department of Radiology, Charing Cross Hospital, Fulham Palace Road, London 
W6 8RF 
Telephone: 020 3311 1234 
Email: henry.tam@nhs.net  
 
Dr Heminder Kaur Sokhi  
The Hillingdon Hospitals NHS Foundation Trust & Paul Strickland Scanner Centre, Mount 
Vernon Hospital  
Telephone: 07545272808 
Email: hsokhi@nhs.net 
 
 
ICTU Operations Manager  
 
Mrs Natalia Klimowska-Nassar  
Imperial College Trials Unit & Division of Surgery 
1st Floor, Stadium House, 68 Wood Lane, London W12 7RH  
 
 
 
 
Tel: 0207 594 3424  
  
 
 
 
 
 
 
 
 
 

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ICTU Study Manager  
 
 
 Statisticians  
 
Dr Francesca Fiorentino 
Imperial College Trials Unit & Division of Surgery 
Imperial College London 
 
Tel: 0 207 594 2614 
Email: f.fiorentino@imperial.ac.uk  
 
Ms Emily Day  
Imperial College Trials Unit  
Imperial College London  
 
Tel: 0207 594 0994 
Email: emily.day@imperial.ac.uk 
 
 
 
 
 
Paula Burak 
Imperial College London 
5L15, Laboratory Block, Charing Cross Campus 
London 
W6 8RP 
 
Email: paula.burak@imperial.ac.uk 
Tel: 
0 203 311 5473   

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ABBREVIATIONS 
 
AE 
Adverse Event 
AI 
Artificial Intelligence 
bp-MRI 
Bi-parametric MRI 
CAD 
Computer Aided Detection 
CWS 
Cancer Worry Scale 
CRF 
Case Report Forms 
CCI 
Charlson Co-Morbidity Index 
CI 
Chief Investigator 
CRN 
Clinical Research Network 
DCE 
Dynamic Contrast-enhancement 
DRE 
Digital Rectal Examination 
DWI 
Diffusion weighted imaging 
GP 
General Practitioner 
HRQoL 
Health-related quality of life 
ISRCTN 
International Standard Randomised Controlled Trial Number 
MCCL 
Maximum cancer core length 
mp-MRI 
Multi-parametric MRI 
PCRMP 
Prostate Cancer Risk Management Programme 
PIS 
Participant Information Sheet 
SAE 
Serious Adverse Event 
SF-12 
12‐item Short‐Form Health Survey 
SOP 
Standard Operating Procedure 
STAI 
State-Trait Anxiety Inventory 
TRUS-biopsy Transrectal ultrasound-guided biopsy 
TSC 
Trial Steering Committee 
 
 

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TABLE OF CONTENT 
 
RESEARCH REFERENCE NUMBERS 
2 
CONTACT LIST 
3 
ABBREVIATIONS 
6 
TRIAL SUMMARY 
10 
 
BACKGROUND 
14 
1.1 Prostate Cancer Screening ............................................................................................ 14 
1.2 Intervention Details ........................................................................................................ 15 
1.2.1 MRI ........................................................................................................................... 15 
1.2.2 Ultrasound ................................................................................................................. 17 
1.2.3 Fluidic Biomarkers ..................................................................................................... 17 
1.2.4 Computer Aided Detection for screening (CAD) ........................................................ 18 
1.3 Recruitment Strategies ................................................................................................... 19 
1.4 Rationale for study ......................................................................................................... 19 
 
OBJECTIVES AND ENDPOINTS 
20 
2.1 Primary Objective ........................................................................................................... 20 
2.2 Other test performance objectives (MRI and US) ........................................................... 20 
2.3 Fluidic Biomarker objectives .......................................................................................... 21 
2.4 Feasibility Objectives ..................................................................................................... 21 
2.5 Reporting and CAD/AI Objectives .................................................................................. 21 
2.6 Other Objectives ............................................................................................................ 21 
2.7 Primary Endpoint ........................................................................................................... 22 
2.8 Performance objectives (MRI and US) ........................................................................... 22 
2.9 Fluidic Biomarker objectives .......................................................................................... 22 
2.10 
Feasibility .................................................................................................................. 22 
2.11 
MRI Reporting and CAD/AI Objectives ...................................................................... 23 
2.12 
Other ......................................................................................................................... 23 
2.13 
Definition of clinically significant cancer ..................................................................... 23 
2.14 
Specification of efficacy parameters .......................................................................... 24 
3. 
STUDY DESIGN 
27 
3.1 Design ........................................................................................................................... 27 
4. 
PARTICIPANT ENTRY 
28 
4.1 Study setting and population .......................................................................................... 28 
4.2 Inclusion and exclusion criteria ...................................................................................... 28 
4.3 Exclusion criteria ............................................................................................................ 28 
4.4 Withdrawal criteria ......................................................................................................... 28 
5 
PROCEDURES AND MEASUREMENTS 
29 
5.1 Identification and recruitment of patients ........................................................................ 29 
5.2 Screening and Pre-randomisation evaluations ............................................................... 31 
5.3 Randomisation and Blinding........................................................................................... 33 
5.4 Visit Schedule ................................................................................................................ 34 
5.5 Study Follow up ............................................................................................................. 35 
5.6 Laboratory Evaluations .................................................................................................. 35 
6. 
INTERVENTION (IF APPLICABLE) 
37 
6.1 Baseline Assessments ................................................................................................... 37 
6.2 Laboratory assessments ................................................................................................ 37 
6.3 BP-MRI and CAD/AI ...................................................................................................... 37 
6.4 Prostate USS ................................................................................................................. 37 
6.5 Questionnaires ............................................................................................................... 38 
6.6 Prostate biopsy .............................................................................................................. 38 
7. 
SAFETY REPORTING 
40 
7.1 Specification of safety parameters ................................................................................. 40 
7.2 Adverse Event (AE) ....................................................................................................... 40 
7.3 Adverse Event recording ................................................................................................ 40 
7.5 Causality of Adverse Events .......................................................................................... 40 

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7.6 Serious Adverse Events ................................................................................................. 41 
7.7 Expected Study-Related Adverse Events ....................................................................... 41 
7.8 Expected Adverse Events Associated with MRI ............................................................. 42 
7.9 Expected Adverse Events Associated with Prostate M-P US ......................................... 42 
7.10 
Expected Adverse Events Associated with Prostate Biopsy ...................................... 42 
7.11 
Reporting of SAEs ..................................................................................................... 43 
7.12 
Related SAEs ............................................................................................................ 43 
7.13 
Unexpected SAEs ..................................................................................................... 43 
7.14 
Reporting of SAEs that are related and unexpected .................................................. 43 
7.15 
Annual reporting of Serious Adverse Events ............................................................. 44 
7.16 
Reporting urgent safety measures ............................................................................. 44 
8. 
DISCONTINUATION & WITHDRAWAL FROM STUDY 
44 
8.1 Study Discontinuation by the sponsor ............................................................................ 44 
8.2 Study Discontinuation by the Chief Investigator ............................................................. 45 
8.3 Study Discontinuation for an individual patient ............................................................... 45 
8.4 Withdrawal from Study ................................................................................................... 45 
9. 
STATISTICAL ANALYSES 
46 
9.1 Sample Size and power considerations ......................................................................... 46 
9.2 Recruitment rates ........................................................................................................... 50 
9.3 Data Analysis ................................................................................................................. 50 
10. 
REGULATORY, ETHICAL AND LEGAL ISSUES 
51 
10.1 
Declaration of Helsinki ............................................................................................... 51 
10.2 
Good Clinical Practice ............................................................................................... 51 
10.3 
Independent Ethics Committee Approval ................................................................... 51 
10.4 
Annual Progress Reports .......................................................................................... 51 
10.5 
Annual Progress Reports and End of Trial Notification .............................................. 51 
10.6 
HRA Approval ........................................................................................................... 52 
10.7 
Other Required Approvals ......................................................................................... 52 
10.8 
Non-Compliance and Serious Breaches .................................................................... 52 
10.9 
Insurance and Indemnity and Sponsor ...................................................................... 52 
10.10 Trial Registration ....................................................................................................... 52 
10.11 Informed Consent ...................................................................................................... 53 
10.12 Contact with General Practitioner .............................................................................. 53 
10.13 Subject Confidentiality ............................................................................................... 53 
10.14 Data Protection and Patient Confidentiality................................................................ 53 
10.15 End of Trial ................................................................................................................ 53 
10.16 Study Documentation and Data Storage ................................................................... 53 
11. 
DATA MANAGEMENT 
55 
11.1 
Source Data .............................................................................................................. 55 
11.2 
Language .................................................................................................................. 55 
11.3 
Database ................................................................................................................... 55 
11.4 
Data Collection .......................................................................................................... 56 
11.5 
Archiving ................................................................................................................... 56 
12. 
STUDY MANAGEMENT STRUCTURE 
57 
12.1 
Trial Steering Committee ........................................................................................... 57 
12.2 
Trial Management Group ........................................................................................... 57 
12.3 
Risk Assessment ....................................................................................................... 57 
12.4 
Monitoring ................................................................................................................. 57 
12.5 
Quality Control and Quality Assurance ...................................................................... 57 
12.6 
Peer review ............................................................................................................... 57 
12.7 
Publication and Dissemination policy ......................................................................... 58 
12.8 
Authorship ................................................................................................................. 59 
13. 
REFERENCES 
60 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
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SIGNATURE PAGE 2 (SPONSOR) 
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SIGNATURE PAGE 3 (STATISTICIAN) 
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IP1 - PROSTAGRAM 
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Sponsor:  
Imperial College London  
V 1.2 01MAY2019 
 
 
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Figure 1: Trial Schema 
Recruitment 
Enrolment  
Follow up 
Recruitment 
 
• Community-based recruitment: (see figure 2 for details) 
• Men aged 50-69 years eligible (see section 4.1 for details) 
Visit 1: Screening Centre 
•
Consented and recruited to the trial 
•
Baseline Questionnaire, IPSS and CCI 
•
HRQoL Questionnaire (SF-12, STAI-6, PBQ + CWS) 
•
Serum PSA. Prostate MRI and Ultrasound 
•
EBQ and PBQ Questionnaires 
•
Optional bio-banking of serum + urine 
Visit 3: End of Study 
•
HRQoL Questionnaire (SF-12, STAI-6, PBQ + CWS) 
•
Participants unblinded to study test results 
•
Patient to follow standard of care according to outcomes of tests 
Visit 2: Prostate Biopsy 
•
HRQoL Questionnaire (SF-12, STAI-6, PBQ + CWS) 
•
Systematic prostate biopsy plus targeted biopsy cores 
in those with a lesion on imaging  
•
Unblind lesion location to operator and allow targeted 
cores to be taken 
Screening  
All tests negative 
(PSA ≤3.0, MRI score 1-2, 
ultrasound score 1-2) 
Test positive 
(PSA ≥3.0, MRI score 3-
5, ultrasound score 3-5) 
Biopsy  
 
 
 

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Protocol No: 
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Sponsor:  
Imperial College London  
V 1.2 01MAY2019 
 
 
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TRIAL SUMMARY 
 
TITLE 
PROSTAGRAM: PROstate Cancer Screening Trial using A Group of 
Radiological Approaches including MRI and ultrasound 
AIM 
To assess the role of using image-based biomarkers in the community 
to screen for clinically significant prostate cancer in men 
PRIMARY 
OBJECTIVES 
To determine the positive test rate of prostate MRI in the general male 
population aged 50 to 69 years 
SECONDARY 
OBJECTIVES 
Other performance objectives 
To determine the prevalence of positive test rate of prostate 
ultrasound in the general male population aged 50 to 69 years 
To determine the distribution of MRI and US scores in a screened 
population  
To evaluate a suitable threshold score that defines positivity of MRI or 
US in a screening population 
To estimate the overall agreement between Prostate specific antigen 
(PSA), US and MRI in the proportion of men with a positive result. 
Then to compare the overall agreement in proportion of men 
diagnosed with clinically significant prostate cancer on biopsy. 
To explore combinations and sequences of prostate MRI, US and PSA 
that might be an optimal screening strategy to evaluate in a future 
definitive study 
To estimate the overall agreement of Imaging findings, PSA and 
Digital rectal examination (DRE) 
To report the clinical outcomes of men with a positive PSA, US and/or 
MRI result 
 
Fluidic Biomarker objectives 
To determine the positive test rate and the distribution of biomarker 
panel scores in the general male population aged 50 to 69 years 
To collect and store serum and urine samples in a biobank to evaluate 
new serum biomarkers 
 
Feasibility Objectives 
To evaluate the feasibility of undertaking a screening cohort study 
comparing the diagnostic performance of prostate MRI and/or US 
and/or serum prostate specific antigen (PSA) testing 
To determine the recruitment rates to the study across different ethnic 
groups  
To determine the eligibility rates across each screening test 
To determine the compliance/retention of participants with study 
processes 

IP1 - PROSTAGRAM 
Protocol No: 
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Imperial College London  
V 1.2 01MAY2019 
 
 
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To assess the acceptability of study processes and informational 
content. 
To estimate the costs of undertaking a subsequent diagnostic paired 
cohort validating study 
 
MRI Reporting and CAD/AI Objectives 
To evaluate the diagnostic performance of a CAD/AI algorithm as a 
standalone reader  
To evaluate the effect of CAD/AI as a second reader on diagnostic 
performance of radiologists 
To evaluate the effect of CAD/AI on interobserver variability of 
radiological interpretation of prostate MRI 
To define a suitable threshold MAI score to detect clinically significant 
cancer 
 
Other Objectives 
To determine the health-related quality of life outcomes 
To assess risk perception and prostate cancer worry and anxiety of 
prostate cancer during the study  
To establish the prevalence of post-biopsy adverse events 
To collect the long-term health outcomes of those men who consent 
to longitudinal follow-up  
To build a databank of ultrasound and MRI meta-files matched with 
histopathology for future research and education 
DESIGN 
A prospective cross-sectional study assessing the feasibility of using 
imaging as a screening test for clinically significant prostate cancer in 
men from the community 
Please note: Study tests are blinded to the reporters. 
SAMPLE SIZE 366 (406 with dropouts)  men aged between 50 and 69 years inclusive 
INCLUSION/ 
EXCLUSION 
CRITERIA 
Participants must be fit to undergo all procedures listed in the protocol 
Estimated life expectancy of 10 years or more 
No PSA test or prostate MRI within the prior two years of 
screening/consent visit 
No previous history of prostate cancer, prostate biopsy or treatment 
for prostate cancer.  
No evidence of a urinary tract infection or history of acute prostatitis 
within the last 6 months 
MAIN 
STUDY 
PROCEDURES 
Main procedures include 
1. Serum PSA  
2. Prostate MRI 
3. Prostate shearwave ultrasound 
4. Serum biomarker panel 

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5. Blood / urine for biobanking (Optional) 
6. If MRI or US positive: Systematic prostate biopsy (10-12 core 
transrectal or transperineal) plus targeted biopsy cores in those 
with a MRI lesion (score 3-5) 
Duration: The total duration of this study will be up to 24 months 
 
PRIMARY 
ENDPOINTS 
The proportion of men with a positive MRI defined by a score of 3 or 
greater 
SECONDARY 
ENDPOINTS 
Other performance objectives (MRI and US) 
The proportion of men with screen-positive prostate ultrasound 
defined by a score of 3 or greater  
The proportion of participants within each MRI score or US score of 1, 
2, 3, 4 or 5 
An evaluation of proportion of participants across each MRI and US 
score with no cancer, insignificant cancer and significant cancer with 
each test.  
A comparison of the proportion of participants with a positive result for 
each screening test. A comparison of the proportion of men 
subsequently diagnosed with a clinically significant prostate cancer as 
defined by pre-specified histological definitions  
Comparison of different testing combinations in terms of biopsy rates, 
detection of insignificant cancer and significant cancers  
The correlation between imaging findings and DRE 
The proportion of men who go onto definitive local or systemic 
treatment. In men who undergo radical prostatectomy the proportion 
who are upgraded at final histology  
 
Fluidic Biomarker objectives 
The proportion of participants within a positive Episwitch biomarker 
panel and distribution of score  
To establish a biobank of fluidic samples matched with histopathology 
for future research 
 
Feasibility Objectives 
Feasibility will be measured based on a point-estimate of recruitment 
rates across different recruitment strategies. Recruitment rates will be 
defined as the number of individuals who: 
i. 
Contact the study team with an expression of interest in 
participation 
ii. 
Attend the screening clinic 
iii. 
Offer informed consent and are enrolled into the study 
The proportion of men from different ethnic groups accepting the initial 
invitation to participate and subsequently participating within the study 

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Eligibility will be assessed against pre-defined eligibility criteria. The 
reasons for ineligibility will be recorded and compared across each 
screening test  
The retention/compliance rate will be defined as the number of 
participants completing screening tests and any follow-up biopsy 
recommendation. The reasons for withdrawal will be documented with 
an optional survey offered to individuals.  
The individual costs for recruitment and screening will be recorded in 
a resource utilisation log. These will be scaled up to provide an 
estimate of the cost for the subsequent study 
 
MRI Reporting and CAD/AI Objectives 
Sensitivity analysis of the CAD/AI system with histology and/or 
radiologist consensus as the reference standard  
Comparison of radiologist diagnostic performance for detection of 
clinically significant cancer with and without the CAD/AI 
The Interobserver agreement with and without the use of CAD/AI as 
second reader 
Receiver operating characteristic (ROC) to compare the diagnostic 
performance of CAD/AI at different MAI scores  
 
Other Objectives 
Changes in Health-related quality of life (HRQOL) measured by SF-
12 (12‐item Short‐Form Health Survey) at baseline and follow-up 
Changes in worry and anxiety scores measures by Cancer worry scale 
(CWS) and State-Trait Anxiety Inventory (STAI). 
Rates of biopsy related adverse events (infectious complications, 
urinary retention, haematuria requiring admission) 
 Linkage to national database 
An open access secure and quality controlled databank of ultrasound 
and MRI meta-files matched with histopathology for future research 
and education 
 
 
 
 
 
 
 
 
 
 

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 BACKGROUND 
 
 
Prostate cancer is one of the most common causes of cancer death in men, resulting in 
11,300 deaths per year(1). The lifetime risk of dying from prostate cancer among UK men 
is 4.3%(2). Prostate cancer mortality rates are consistently higher than breast cancer 
mortality on an age standardised basis(3). These mortality figures mean that there has been 
a long-standing discussion regarding the introduction of a population-based screening 
program equivalent to the breast cancer-screening program.   
The aim of a screening programme would be to detect clinically significant prostate cancer 
at a curable stage and thereby reduce cancer-specific mortality.  The mortality risk for 
prostate cancer is primarily determined by how advanced the cancer is at diagnosis. The 5-
year survival for men with distant metastases is 30% but if diagnosed when localised to the 
prostate the 5-year survival rate is equivalent to the general population(2). Localised disease 
is generally asymptomatic and there is a long latent period between the early malignant 
phase and progression to metastatic cancer. These characteristics mean that a successful 
screening programme has potential to significantly improve prostate-cancer specific 
mortality by detecting the disease at an earlier stage prior to progression to metastatic 
disease. 
There is high-quality evidence from the large European Randomised Study of Screening for 
Prostate Cancer (ERSPC) that prostate cancer screening can reduce prostate cancer 
mortality by at least a relative risk reduction of 21% compared to little to no PSA testing(4). 
However, these mortality benefits need to be considered in view of the potential for harms 
from a population-based screening programme. The UK National Screening Committee (UK 
NSC) has reviewed the updated evidence for prostate cancer screening and recommended 
against a universal screening programme due to the limitations of Prostate-Specific Antigen 
(PSA) as a screening test. The summary report describes PSA as “a poor test for prostate 
cancer and a more specific and sensitive test is needed”(5).  
Due to the limitations of PSA, there is no country or international body, which recommends 
routine PSA screening for all men. Instead, the majority recommend informing men about 
the benefits and risks of PSA screening so that each man can make an informed decision 
with knowledge of the controversy around PSA. The potential risks to be considered include 
false-positives leading to high rates of biopsy, biopsy-related complications and over-
diagnosis of low risk cancer that is then often unnecessarily treated using radical therapy. 
There is a large reservoir of low-risk prostate cancers within the population estimated at 
approximately 1 in 3 of men above the age of 50 years. The detection of such indolent low 
risk disease leads to men being subjected to the harm of a cancer diagnosis and often 
radical treatment that does not confer a survival benefit over a median of 10 years follow-up 
compared to no treatment. Yet, radical therapy confers genito-urinary harms such as 
incontinence, impotence and rectal toxicity. Those men who choose active surveillance 
rather than radical active treatment are then placed on intensive monitoring regimens that 
often include repeated PSA testing, repeat 1-2 yearly biopsies and the potential for 
psychological distress.  

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PSA is unable to reliably discriminate between clinically insignificant and clinically significant 
cancers that pose a threat to quality of life or life expectancy. In the ERSPC study it was 
estimated that 50% of cancers were over-diagnosed and would not have caused any 
morbidity or mortality during the man’s lifetime (6). PSA is also non-specific and can be 
elevated due to benign enlargement of the prostate gland, inflammation or infection, which 
triggers unnecessary biopsies. Due to these problems, it is accepted that the harms of PSA 
screening outweigh the proven mortality benefit from a prostate cancer-screening 
programme.  
This study aims to evaluate the feasibility of a different approach to prostate cancer 
screening that might retain the reductions in mortality whilst minimising the harms hitherto 
seen. 
 
 
 
 
The rapid advances in imaging technology has created potential for new image-based 
screening tests. Prostate MRI has emerged as the dominant technique for diagnosis and 
staging of clinically localised prostate cancer. There has been extensive research into the 
role of prostate MRI in men referred with a suspicion of prostate cancer. The NIHR-
HTA/MRC PROMIS trial was led by the same Chief Investigator of this study(7) and showed 
that it has a high sensitivity and negative predictive value for clinically significant prostate 
cancer while limiting the detection of low-risk cancer in the UK in men who present with an 
elevated PSA in secondary hospital care. These performance characteristics may differ 
when used as a screening test in the community where we would expect a lower prevalence 
of disease and different population characteristics. 
As an image-based screening test, prostate MRI has potential to significantly reduce the 
problem of too many prostate biopsies and over-diagnosis of clinically insignificant cancers. 
A further advantage of image-based screening is that it allows suspicious areas to be 
visualised and targeted with biopsies thus improving the detection of clinically significant 
cancers. Prostate diagnostics are currently widely based on transrectal ultrasound-guided 
(TRUS) biopsy, which involves taking 10–12 biopsy cores through the rectum. This 
technique is blind to the location of the cancer in the prostate, which is in contrast to other 
solid organs cancers where the lesion is identified by imaging in order to direct biopsies to 
the area of suspicion. The random deployment of needles increases the overdiagnosis rate 
and has poor diagnostic performance for ruling in or out clinically significant cancer. This 
technique also carries a risk of infectious complications as the needles transverse the rectal 
mucosa. 
In an imaged-based screening programme, such as in breast cancer mammography for 
instance, the lesion can be visualised thus allowing a targeted biopsy to be performed. A 
targeted biopsy approach has been shown to have improved accuracy, better sampling 
efficiency and reduced histopathological burden in men who present with an elevated PSA 
in secondary care(8). There is some evidence that the reduction in number of cores from 
targeting leads to less pain, fewer LUTS and potentially lower rates of infectious 
complications and sepsis(9). 

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Image-based screening tests have been successfully adopted in other cancer screening 
programmes. Breast mammography for instance is an established screening programme 
across the majority of developed countries and there is mounting evidence for the efficacy 
of CT colonoscopy for bowel cancer screening(10) and lung CT for lung cancer [ref]. 
Although MRI is starting to become a standard investigation in the prostate cancer 
diagnostic pathway in secondary care, there have been a number of small but limited studies 
evaluating its role as a potential screening test in the community.  
 
 
A pilot study embedded within the existing Göteborg arm of the ERSPC screening trial 
reported the diagnostic performance of MRI at different PSA thresholds(11). In this study, 
MRI was used as an adjunct to PSA and the participants did not reflect an average-risk 
screened population as they were recruited from the final screening round and had been 
screened up to 9 times using serum PSA with a third having undergone a previous 
biopsy(11, 12). Under these conditions, when MRI was combined with a low PSA threshold 
of ≥ 1.8ng/ml, the sensitivity was 73% with a negative predictive value of 92% in detecting 
and ruling out Gleason >/=7 cancers. Nam et al(13) carried out a feasibility/pilot study of 
MRI as a potential screening test in the community. Of the 47 recruited men, 18 (38.3%) 
had cancer while 29 (61.7%) had no evidence of cancer. The adjusted OR of prostate 
cancer was significantly higher for MRI score than for prostate specific antigen level (2.7, 
95%CI 1.4-5.4, p=0.004 vs 1.1, 95%CI 0.9-1.4, p=0.21). Among the 30 men with a 
normal PSA (defined as less than 4.0ng/ml) the positive predictive value in those with an 
MRI score of 4 or more was 66.7% (6/9) and the negative predictive value in those with 
an MRI score of 3 or less was 85.7% (18/21, p=0.004). 
The NIHR-HTA/MRC PROMIS trial used a multi-parametric MRI (mp-MRI) technique, which 
combined anatomical T2-weighted imaging with functional techniques such as diffusion-
weighted imaging (DWI) and dynamic contrast-enhanced (DCE) sequences.  This protocol 
requires the administration of intra-venous contrast and 30-40 minutes scanning time. A 
screening MRI will need to be short duration and free of any intravenous contrast agent. The 
initial results from shorter non-contrast biparametric-MRI (bp-MRI) protocols are 
encouraging and suggest that fast protocols with image acquisition times of under 15 
minutes without contrast can have a similar diagnostic performance to standard mp-MRI in 
a pre-biopsy setting(14). This is supported by several meta-analyses which have suggested 
that there is little to no incremental benefit from adding dynamic contrast sequences(15, 16) 
and the most recent PI-RADS v2 guidelines commented that the added value of DCE has 
not been firmly established(17). The guidelines acknowledge that elimination of DCE may 
be the next logical step once there is high-quality evidence to support this decision(18). 
At present, the role of DCE in PIRADSv2 has been restricted to assessment of indeterminate 
lesions in the peripheral zone. Within a screening protocol, the follow-up for indeterminate 
lesions may be surveillance or based on a patient-recall system, which further limits the role 
of DCE with a potential screening test based on MRI. The benefits of a non-contrast 
approach has been investigated by the chief investigator (CI) of this study in the PICTURE 
study. This subanalysis found that the incremental benefit of contrast was marginal in men 
who had previously undergone TRUS biopsy(19). There was no significant improvement in 
sensitivity from the addition of DCE but it did reduce specificity which would be expected as 

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there are a number of benign conditions which trigger false positives on DCE including focal 
prostatitis and mixed BPH nodules in the central gland(20). The PICTURE study validated 
each mp-MRI sequence against transperineal template mapping biopsy.  
Certainly, the higher acquisition times and the risk of contrast enhancement from the 
gadolinium at a population level make it unfeasible to incorporate. An image-based 
screening protocol needs to be simple and practical without significantly affecting the 
accuracy of the test. It is not practical within a screening programme to verify all participants’ 
renal function, gain intravenous access and administer contrast.  
The omission of DCE shortens examination time and once the need for contrast is 
eliminated, many of the practical challenges associated with mp-MRI are removed and 
scans can be performed across a wider range of locations and times. 
 
 
There are newer ultrasound techniques emerging, which have a number of potential 
advantages compared to MRI. Ultrasound imaging is lower cost, more accessible and 
operators are widely available Conventional grey-scale ultrasound is a mainstay within 
prostate cancer diagnostics as it is used to visualise the prostate in order to guide biopsies 
in zones of the prostate. The standard grey-scale or b-mode imaging has limited sensitivity 
and specificity for detection of significant prostate cancer (21, 22). 
There have been growing interest in combining b-mode ultrasound with additional modalities 
such as elastography, which is a technique, used for the cancer detection based on tissue 
stiffness. It is known that malignant tissue is less elastic due to increased cell density and 
differing collagen distribution. 
Shearwave elastography (SWE) is a novel type of elastography presses tissue using 
acoustic radiation force, measuring the speed of progress of the resultant shear wave. In 
contrast to other ultrasound techniques, which are non-quantitative, SWE provides an 
absolute numerical result, which can generate a threshold for screening. It is also avoids the 
technical challenge and learning associated with manual tissue compression with standard 
elastography are avoided.  A meta-analysis of SWE has shown a combined sensitivity of 
84% and specificity 86% for detection of prostate cancer(23) 
 
 
There are fluidic biomarkers that might also allow men at risk to consider avoiding an 
immediate biopsy. The advantage of a blood-based biomarker lies in the simplicity, 
reproducibility and non-invasiveness of the test. These biomarkers and biomarker panels 
have also shown the ability to reduce the risk of diagnosing clinically insignificant lesions 
whilst identifying some clinically significant cancers. Studies in this area have some 
limitations with heterogeneous populations, use of different thresholds for defining a 
suspicious test and using TRUS-biopsy as the reference standard (24, 25). Nonetheless, 
the 4-kallikrein and phi fluidic biomarker panels might allow up to 24%-42% and 29%-36% 
men to avoid biopsy whilst missing 6%-12% and 9%-10% significant (Gleason >/=7) 
cancers, respectively (26-30). Some, such as phi and PCA3, have not been convincing when 
compared to an imaging-based pathway (31). Others have recently been found to work in a 
complementary manner to MRI raising the prospect of further refinements to decisions about 
whether to biopsy(32).  

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There has been widespread interest in novel biomarkers as an alternative or adjunct to PSA 
screening. A range of urine tests and plasma protein biomarkers have been proposed to 
address the limitations of PSA(33). We will incorporate an optional biobanking of blood 
following standard operating protocols so that novel biomarker panels can either be 
developed and/or tested within the cohort of men in this study.  
 
 
We will prospectively test the Episwitch biomarker panel. There are multiple genetic changes 
associated with prostate cancer, including mutations in p53 (up to 64% of tumours), p21 (up 
to 55%), p73 and MMAC1/PTEN tumour suppressor genes, but these mutations do not 
explain all the observed effects on gene regulation [8]. In human cells, epigenetic 
mechanisms involving dynamic and multi-layered chromosomal loop interactions are 
powerful regulators of gene expression [9]. Chromosome conformation capture (3C) 
technologies allow these signatures to be recorded and have gained considerable attention 
for disease diagnosis [10-13]. 
A significant proportion of chromosomal conformations are controlled by non-coding RNAs, 
which regulate the tumour-specific conformations [14]. Tumour cells have been shown to 
secrete non-coding RNAs that are endocytosed by neighbouring or circulating cells and 
change their chromosomal conformations in a process called “horizontal transfer” [15, 16]. 
RNA in blood has low stability and poor detection rates. Circulating DNA present in plasma 
does not retain 3D conformational topological structures present in the intact cellular nuclei.  
Prostate tumours undergo long-range epigenetic alterations in 3-dimension chromosome 
conformations and distinct epigenetic signatures were found in circulating DNA from PCa 
patients [17]. Previous work has shown the presence of melanoma-specific chromatin 
conformations in peripheral blood mononuclear cells (PBMCs) and primary tumours of 
melanoma patients [18, 19]. Fractionation studies showed that the detected signature comes 
from lymphocytes and not circulating tumour cells [18]. 
The Episwitch assay is a next generation assays detects epigenetic regulatory signature 
changes in the structures of chromosomes at the loci implicated in the onset and progression 
of the disease. 
 
 
An image-based national screening programme requires a large scanning capacity and 
produces many scans requiring interpretation by radiologists with the relevant experience 
and subspecialty training. It is important that a screening prostate MRI provides consistent 
results when performed across diverse centres and interpreted by different clinicians. There 
is interobserver variability in all radiological reporting but the rates for prostate MRI have not 
reached the level achieved with mammograms for breast cancer screening(34). 
Computer-aided detection (CAD) or Artificial Intelligence (AI) systems can potentially be an 
utilised to reduce interobserver variability and improve radiological reporting capacity. The 
CAD/AI system acts as a supplement to human readers and marks potential areas of 
concern so the radiologist can decide if the area warrants further investigation. It can assist 
radiologists to identify cancers, which might otherwise be missed. There has been 
widespread use of CAD/AI systems in breast cancer screening programs particularly in the 
United States’ Medicare population where it is estimated it is used in 74% of screening 

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mammograms(35). There is extensive evidence that the system can improve the sensitivity 
of mammography and improve radiology reporting workflow (36). CAD/AI systems are being 
investigated in other image-based screening modalities particularly CT-colonography with 
encouraging results(37).  
 
 
There are similar CAD/AI systems available for prostate MRI and in the early stage of 
validation (38). The PROSTAGRAM study will embed a CAD/AI application to prospectively 
evaluate the feasibility of using a CAD/AI system within the workflow of radiological 
interpretation.  
 
 
Screening tests are targeted at a large population of asymptomatic individuals, the majority 
of whom are healthy and do not have the target disease. The low prevalence of positive 
findings from screening necessitate a large sample size to evaluate performance 
characteristics of screening tests. Potential participants are recruited direct from the 
community, which requires different strategies to trials recruiting within existing clinical 
pathways. 
The PROSTAGRAM trial will evaluate various recruitment pathways in order to establish the 
optimum recruitment strategy and identify potential barriers to recruitment. These include 
postal, sms, poster, websites and direct opportunistic approaches via the general 
practitioner.  
Previous prostate cancer screening trials have used written invitations with subsequent 45% 
response rate to attend a prostate cancer-screening clinic (39). This is lower than the uptake 
for breast and cervical screening which have uptake rates consistently above 70%, although 
these are in the context of a national screening programme with extensive resources, 
advertising and public acceptance.  A low uptake can have significant impact on the external 
validity of a screening test(40). 
In addition, previous large screening trials have had a low screening uptake among certain 
ethnic groups. African/African-Caribbean men have been particularly under-represented in 
previous trials despite being at double the risk of mortality from prostate cancer (41). The 
current screening strategies are based on recommendations from studies of predominately 
Caucasian men despite the clear evidence that African/African-Caribbean men have a high 
lifetime risk of prostate cancer mortality. There is a need for further screening research in 
this population and the PROSTAGRAM study aims to achieve a participant recruitment 
which is representative across ethnic risk groups particularly African/African-Caribbean 
men. 
 
 
The UK National Screening Committee has recommended that further research is required 
into alternative screening tests before a population-based prostate cancer screening 
programme can be considered for approval(42). We propose that prostate MRI has certain 
performance characteristics, which make it attractive as a potential screening test. We have 
previously shown that prostate is a reliable pre-biopsy triage test in secondary care once 

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men have been referred to hospitals for an elevated serum PSA. However, its role as a 
screening test is unknown and warrants further investigation.  
Our long-term objective is to evaluate whether a screening prostate MRI could be an 
alternative or complementary image-based screening test to PSA.  
The current study has not been designed to establish the sensitivity and specificity of MRI 
as this has would require all participants to undergo a prostate biopsy as the reference 
standard for determining the presence of prostate cancer. It would not be appropriate in a 
screening study to require all participants to have a biopsy particularly when the diagnostic 
performance of prostate MRI has been well established in secondary care with prostate 
biopsy as the reference standard. 
Instead, the primary objective will be to establish the prevalence of screen-positive prostate 
MRI in the general male population aged 50-69 years and collect information on the 
feasibility of a larger scale study. The results of this study will inform the design of a large 
diagnostic paired cohort validating study comparing PSA and MRI and other potential 
imaging or fluidic biomarkers. The subsequent study requires a large sample size and 
resource commitment due to the low prevalence of prostate cancer in a screened population. 
In this study, we will obtain point estimates on the prevalence of a suspicious test that 
triggers a biopsy; such information is currently not available and is required to inform the 
design and sample size calculations of the larger clinical study. This study will also evaluate 
the feasibility of a large screening MRI trial. We will optimise recruitment strategies and 
identify potential barriers to recruitment.   
 OBJECTIVES AND ENDPOINTS 
 
To determine the positive test rate of prostate MRI in the general male population aged 
50 to 69 years 
 
 
 
1. To determine the prevalence of positive test rate of prostate ultrasound in the 
general male population aged 50 to 69 years 
 
2. To determine the distribution of MRI and US scores in a screened population  
 
3. To evaluate a suitable threshold score that defines positivity of MRI or US in a 
screening population 
 
4. To estimate the overall agreement between PSA, US and MRI in the proportion of 
men with a positive result. Then to compare the overall agreement in proportion of 
men diagnosed with clinically significant prostate cancer on biopsy. 
 

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5. To explore combinations and sequences of prostate MRI, US and PSA that might 
be an optimal screening strategy to evaluate in a future definitive study 
 
6. To estimate the overall agreement of Imaging findings, PSA and DRE 
 
7. To report the clinical outcomes of men with a positive  PSA, US and/or MRI result 
 
 
 
1. To determine the positive test rate and the distribution of biomarker panel scores in 
the general male population aged 50 to 69 years 
2. To collect and store serum and urine samples in a biobank to evaluate new serum 
biomarkers 
 
 
 
1. To evaluate the feasibility of undertaking a screening cohort study comparing the 
diagnostic performance of prostate MRI and/or US and/or serum prostate specific 
antigen (PSA) testing 
 
2. To determine the recruitment rates to the study across different ethnic groups  
 
3. To determine the eligibility rates across each screening test 
 
4. To determine the compliance/retention of participants with study processes 
 
5. To assess the acceptability of study processes and informational content. 
 
6. To estimate the costs of undertaking a subsequent diagnostic paired cohort 
validating study 
 
 
 
1. To evaluate the diagnostic performance of a CAD/AI algorithm as a standalone 
reader  
 
2. To evaluate the effect of CAD/AI as a second reader on diagnostic performance of 
radiologists 
 
3. To evaluate the effect of CAD/AI on interobserver variability of radiological 
interpretation of prostate MRI 
 
4. To define a suitable threshold MAI score to detect clinically significant cancer 
 
 
 
1. To determine the health-related quality of life outcomes 
 

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2. To assess risk perception and prostate cancer worry and anxiety of prostate cancer 
during the study  
 
3. To establish the prevalence of post-biopsy adverse events 
 
4. To collect the long-term health outcomes of those men who consent to longitudinal 
follow-up  
 
5. To build a databank of ultrasound and MRI meta-files matched with histopathology 
for future research and education  
 
 
The proportion of men with a screen-positive MRI defined by a score of 3 or greater.  
 
1. The proportion of men with screen-positive prostate ultrasound defined by a score of 
3 or greater  
 
2. The proportion of participants within each MRI score or US score of 1, 2, 3, 4 or 5 
 
3. An evaluation of proportion of participants across each MRI and US score with no 
cancer, insignificant cancer and significant cancer with each test.  
 
4. A comparison of the proportion of participants with a positive result for each screening 
test. A comparison of the proportion of men subsequently diagnosed with a clinically 
significant prostate cancer as defined by pre-specified histological definitions  
 
5. Comparison of different testing combinations in terms of biopsy rates, detection of 
insignificant cancer and significant cancers  
 
6. The correlation between imaging findings and DRE 
 
7. The proportion of men who go onto definitive local or systemic treatment. In men who 
undergo radical prostatectomy the proportion who are upgraded at final histology 
 
 
1. The proportion of participants within a positive Episwitch biomarker panel and 
distribution of score  
2. To establish a biobank of fluidic samples matched with histopathology for future 
research 
 
 
1. Feasibility will be measured based on a point-estimate of recruitment rates across 
different recruitment strategies. Recruitment rates will be defined as the number of 
individuals who: 
i. 
Contact the study team with an expression of interest in participation 
ii. 
Attend the screening clinic 
iii. 
Offer informed consent and are enrolled into the study 

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These results will enable a prediction of number of General Practitioner (GP) practices 
and length of time needed to recruit the required number of patients for a future trial.  
 
2. The proportion of men from different ethnic groups accepting the initial invitation to 
participate and subsequently participating within the study 
 
3. Eligibility will be assessed against pre-defined eligibility criteria. The reasons for 
ineligibility will be recorded and compared across each screening test  
 
4. The retention/compliance rate will be defined as the number of participants 
completing screening tests and any follow-up biopsy recommendation. The reasons 
for withdrawal will be documented with an optional survey offered to individuals.  
 
5. The individual costs for recruitment and screening will be recorded in a resource 
utilisation log. These will be scaled up to provide an estimate of the cost for the 
subsequent study 
 
 
1. Sensitivity analysis of the CAD/AI system with histology and/or radiologist consensus 
as the reference standard  
2. Comparison of radiologist diagnostic performance for detection of clinically significant 
cancer with and without the CAD/AI 
3. The Intraobserver agreement with and without the use of CAD/AI as second reader 
4. Receiver operating characteristic (ROC) to compare the diagnostic performance of 
CAD/AI at different MAI scores  
 
 
1. Changes in HRQOL measured by SF-12 and at baseline and follow-up 
2. Changes in worry and anxiety scores measures by CWS and STAI. 
3. Rates of biopsy related adverse events (infectious complications, urinary retention, 
and haematuria requiring admission) 
4. Linkage to national database 
5. An open access secure and quality controlled databank of ultrasound and MRI meta-
files matched with histopathology for future research and education 
 
 Clinically significant cancer will be defined across a range of histological thresholds 
including  
i. 
Any length of Gleason >/=3+4 
ii. 
Any length of Gleason >/=4+3 
iii. 
UCL/Ahmed definition 1 (Gleason >/=4+3 and/or Maximum cancer core length 
>/=6mm). 
iv. 
UCL/Ahmed definition 2: Gleason >/=3+4 and/or Maximum cancer core length 
>/=4mm 
v. 
Gleason >/=3+4 and/or Maximum cancer core length (MCCL) >/=6mm  

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OBJECTIVES 
EFFICACY 
PARAMETER 
TIME POINT & TOOL 
Primary Objectives 
 
 
To determine the prevalence of 
screen-positive prostate MRI scans 
in the general male population aged 
50 to 69 years  
The proportion of men 
with a screening MRI 
score of 3 or greater 
Visit 1 
MRI reporting form 
Secondary Objectives 
 
 
OTHER TEST PERFORMANCE OBJECTIVES (MRI AND US) 
To determine the prevalence 
of positive test rate of US 
The proportion of men 
with a screening US 
score of 3 or greater 
Visit 1: 
US reporting form 
To establish the distribution of 
MRI and US scores in a 
screened population 
The proportion of men 
across 
each 
MRI 
score 
Visit 1:  
MRI & US reporting 
form 
To establish a threshold score 
that defines positivity of MRI 
and 
US 
in 
a 
screened 
population 
Comparison of false 
positives 
& 
false 
negatives across each 
MRI & US scores 
Visit 1 & 2:  
MRI, US and biopsy 
reporting form 
The 
overall 
agreement 
between PSA, US and MRI in 
the proportion of men with a 
screen positive result. 
The proportion with a 
positive result for each 
screening test 
Visit 1  
PSA, US and MRI 
reporting form 
The 
overall 
agreement 
between PSA, US & MRI in 
proportion of men diagnosed 
with 
clinically 
significant 
prostate cancer on biopsy. 
The 
proportion 
diagnosed 
with 
a 
clinically 
significant 
prostate 
cancer 
as 
defined histologically 
Visit 1 & 2:  
PSA, MRI and biopsy 
reporting form 
To explore combinations & 
sequences of MRI, US and 
PSA  
Comparison of biopsy 
rates, 
detection 
of 
insignificant/significant 
cancer 
Visit 1 
PSA, 
MRI, 
US 
reporting form 
To estimate overall imaging 
findings and DRE 
Correlation 
between 
imaging & DRE 
Visit 1 & 2 
MRI, US & DRE form 
To 
report 
the 
clinical 
outcomes of men with any 
positive test result 
The proportion who 
undergo treatment. If 
RRP the proportion 
upgraded 
at 
final 
histology 
Visit 1-3: 
PSA, MRI and biopsy 
reporting 
form. 
Treatment  outcomes 

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OBJECTIVES 
ENDPOINT 
TIME POINT & TOOL 
FLUIDIC 
BIOMARKERS
To establish the positive test 
rate 
and 
distribution 
of 
biomarker panel scores 
The 
proportion 
of 
men with a positive 
Episwitch biomarker 
panel and score 
Visit 1: 
Biomarker 
panel 
reporting form 
To establish a biobank of 
fluidic samples matched with 
histopathology 
for 
future 
research 
Total number of men 
providing specimens 
to 
the 
tissue 
biomarker 
Visit 1: 
Biobank entry log 
FEASIBILITY 
To evaluate the feasibility of a 
screening 
cohort 
study 
investigating the diagnostic 
performance of prostate MRI 
vs. PSA 
Descriptive statistics 
of recruitment rates  
 
Visits 1 & 2: 
Recruitment log/form 
To determine the recruitment 
rates across different ethnic 
groups 
Proportion of men 
from different ethnic 
groups recruited to 
study 
Visit 1 & 2: 
Recruitment log/form 
To determine the eligibility rate 
across each screening test 
The number of men 
with 
reasons 
for 
ineligibility 
Visit 1:  
Recruitment log 
To determine the compliance/ 
retention of participants with 
study processes 
Number 
of 
men 
completing tests & 
follow 
up 
recommendations 
Visits 1-3:  
Recruitment log/form 
The acceptability of study 
processes and informational 
content 
Thematic analysis of 
interviews and free 
texts 
Acceptability 
Questionnaires  
The costs of undertaking a 
diagnostic 
paired 
cohort 
validating study 
Scaled up costs of 
recruitment 
& 
screening 
Resource utilisation log 

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OBJECTIVES 
ENDPOINT 
TIME POINT & TOOL 
CAD/AI 
To 
evaluate 
diagnostic 
performance of a CAD/AI 
algorithm as a standalone 
reader 
to 
detect 
clinically 
significant prostate cancer on 
MRI   
Sensitivity analysis of 
the CAD/AI system 
with 
biopsy 
or 
consensus 
as 
the 
reference standard 
Visit 1 & 2:  
MRI, CAD and biopsy 
reporting form 
To evaluate the effect of 
CAD/AI as a second reader on 
diagnostic performance of the 
radiologist   
Comparison 
of 
diagnostic 
performance 
of 
radiologists with and 
without CAD 
Visit 1 & 2:  
MRI, CAD and biopsy 
reporting form 
To evaluate the effect of 
CAD/AI 
on 
interobserver 
variability 
of 
radiological 
interpretation of prostate MRI  
Interoberver 
agreement quantified 
Visit 1 & 2:  
MRI, CAD and biopsy 
reporting form 
To define a suitable threshold 
MAI score to detect clinically 
significant cancer 
ROC 
comparing 
diagnostic 
performance 
of 
CAD/AI at different 
MAI scores 
Visit 1 & 2:  
CAD output and biopsy 
reporting time 
OTHER 
To 
determine 
the 
health-
related quality of life outcomes 
Change to SF-12 at 
baseline and follow-
up 
Visit 1, 2 & 3: 
Questionnaires 
at 
baseline and follow-up 
To 
evaluate 
the 
risk 
perception 
and 
prostate 
cancer worry and anxiety  
Change 
in 
risk 
perception, 
STAI, 
CWS at baseline & 
follow-up 
Visit 1, 2 & 3 
Questionnaires 
at 
baseline and follow up 
To determine the rates of 
biopsy related adverse events 
Rates 
of 
biopsy 
related 
adverse 
events 
Visit 3: 
Adverse 
events 
reporting form 
To collect the long-term health 
outcomes  
Linkage via national 
database 
Optional follow-up of 
consented 
To 
build 
a 
databank 
of 
ultrasound and MRI meta-files 
matched with histopathology 
for 
future 
research 
and 
education 
Upload 
rate 
to 
databank 
Visit 1: 
Databank entry log of 
mp-USS and mp-MRI 
meta-matched files 

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Recruitment 
Enrolment  
Follow up 
Recruitment 
 
• Community-based recruitment: (see figure 2 for details) 
• Men aged 50-69 years eligible (see section 4.1 for details) 
Visit 1: Screening  
•
Consented and recruited to the trial 
•
Baseline Questionnaires  +IPSS + CCI 
•
HRQoL Questionnaire (SF-12, STAI-6, PBQ + CWS) 
•
Serum PSA. Prostate MRI and Ultrasound 
•
EBQ and PBQ Questionnaires 
•
Optional bio-banking of serum + urine 
Visit 3: End of Study 
•
HRQoL Questionnaire (SF-12, STAI-6, PBQ + CWS) 
•
Participants unblinded to study test results 
•
Patient to follow standard of care according to outcomes of tests 
Visit 2: Prostate Biopsy 
•
HRQoL Questionnaire (SF-12, STAI-6, PBQ + CWS) 
•
Systematic prostate biopsy plus targeted biopsy 
cores in those with a lesion on imaging  
•
Unblind lesion location to operator and allow 
targeted cores to be taken 
Screening  
All tests negative 
(PSA ≤3.0, MRI score 1-2, 
ultrasound score 1-2) 
Test positive 
(PSA ≥3.0, MRI score 3-5, 
ultrasound score 3-5) 
Biopsy  
3. STUDY DESIGN  
 
 
A prospective cross-sectional screening study with a built-in feasibility assessment of a 
diagnostic cohort study. 
The study design has been developed in accordance with STROBE (Strengthening the 
Reporting of Observational Studies in Epidemiology) guidelines (43) and the 
Consolidated Standards of Reporting Trials (CONSORT) statement (44). 
 
 
 
 
 

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4. PARTICIPANT ENTRY 
 
Men aged between 50 and 69 years at average risk of prostate cancer based in the 
community will be invited to participate 
 
 
Inclusion criteria 
1. Men aged between 50 and 69 years inclusive at the time of study entry 
2. Participants must be fit to undergo all procedures listed in the protocol 
3. Estimated life expectancy of 10 years or more 
4. An understanding of the English language sufficient to understand written and 
verbal information about the trial and consent process 
5. Participants must be willing and able to provide written informed consent  
 
 
1. Previous PSA test or prostate MRI within the prior two years of screening/consent 
visit 
2. Evidence of a urinary tract infection or history of acute prostatitis within the last 6 
months 
3. Previous history of prostate cancer, prostate biopsy or treatment for prostate cancer 
(interventions for benign prostatic hyperplasia/bladder outflow obstruction is 
acceptable) 
4. Any potential contraindication to MRI, including but not limited to: 
a. Devices or metallic foreign bodies such as pacemakers, implantable 
defibrillators, neurostimulators, cochlear implants, coronary stents, prosthetic 
heart valves, aneurysm clips and other intravascular devices  
b. Previous history of hip replacement surgery, metallic hip replacement or 
extensive pelvic orthopaedic metal  
c. Claustrophobia 
5. Any potential contraindication to prostate biopsy 
6. Dementia or altered mental status that would prohibit the understanding or rendering 
of informed consent.  
7. Any other medical condition precluding procedures described in the protocol 
 
 
Inability to conduct any one of the imaging tests, blood tests or biopsies according to 
protocol.  
 
 

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5 PROCEDURES AND MEASUREMENTS  
 
 
5.1.1 GP Practice Recruitment 
GP practices will be recruited from each individual study region. The initial recruitment will 
be from practices within the North West London study region in collaboration with the NIHR 
Clinical Research Network North West London (CRN NWL). The CRN NWL will approach 
GP practices, and the study team GP practices will continue to be added to ensure the 
sample size is achieved. Anonymised data will be extracted from all participating practice 
computer systems related to the demographics of the practice population. This data will be 
used to describe the general practice population and ensure that recruitment is 
representative across each practice.  
 
5.1.2 Participant Recruitment 
Figure 2 summarises the recruitment flow chart. A number of approaches will be used to 
inform potential participants about the trial and undertake recruitment: 
 
Postal invitation 
For practices using the postal invitation approach, potential participants will be identified 
from the GP practice registers. The practice database will be searched using pre-defined 
eligibility criteria including PSA results, history of prostate cancer and the presence of other 
co-morbidities. This data will be used to assess the patient’s suitability to participate, 
including whether the patient’s co-morbidity and/or frailty means that an individual’s life 
expectancy would limit their benefit from screening or other reasons why it may be 
inappropriate for the patient to receive an invitation.  
Participants deemed eligible will be sent an SMS or invitation letter with an enclosed leaflet 
depending on the GP practice policy. Research shows that the majority of participants make 
their informed decision on whether to participate in research based on shortened first level 
information(45). The participation postal recruitment procedures are detailed in a Standard 
Operating Procedure (SOP Postal Recruitment). Non-responders may be sent up to one 
reminder and/or telephone call or SMS message via the general practitioner depending on 
the services available in each surgery. The patient list will be used to provide basic, 
anonymised information regarding non-responders for comparison with the recruited cohort. 
This will enable some assessment of how representative the recruited cohort is for each GP 
Practice. 
 
Opportunistic recruitment:  
In practices using opportunistic recruitment, eligible individuals presenting to their GP for a 
routine consultation will be informed about the study and invited to participate. Potential 
participants may also be opportunistically approached by their GP during a home visit. The 
GP will check eligibility criteria and discuss the basic structure of the study. If the individual 
is interested, they will be offered an invitation letter directly along with the documents listed 

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above and asked to contact the study team. Posters and flyers may also be put on display 
at participating GP surgeries 
 
Supplementary Recruitment strategies 
We will publicise the study in the local area using posters and flyers. These may be 
displayed.  
 
1. By Prostate Cancer Charities or organisations/individuals with an interest in 
prostate cancer. Examples of the organisation could include Prostate Cancer UK, 
Maggie’s support group, Pelican Cancer Foundation, and other relevant 
organisations.   
 
2. In select local areas frequented by our target group (e.g. community groups 
libraries, gyms) and in local newspapers 
 
3. On the PROSTAGRAM website and social media pages. 
Additional methods of recruitment will be via awareness meetings with community 
groups as well as media and press events.  
 
Potential participants who contact the research team will discuss the trial in more detail over 
the telephone. The study co-ordinator will keep a screening and enrolment log of all 
participants being considered for the trial.  
During the telephone discussion, the study team will explain more detail regarding the trial 
and check that the participants meets the inclusion criteria. If the person is interested in 
participating in the study the patient information sheet will be posted and/or emailed to them. 
A screening log will be kept and if a person does not wish to participate in the trial, the 
reasons for this should be recorded.  
All potential participants who are interested in the study will be invited to the screening centre 
where the trial be re-discussed. Everyone will receive the Participant Information Sheet (PIS) 
at least 24 hours in advanced as per national standards to allow time to consider whether 
they want to participate in the study. The PIS will emphasise that if they do not want to 
participate in the study they are still eligible for a PSA screening test following discussion of 
the risks and benefits with their GP as part of the opportunistic PSA screening in the UK. 
The PIS will also contain contact details of the study co-ordinator who can be contacted if 
the participant has any additional questions about the study. The information pack may also 
include questionnaires for prior completion.  
Individuals who are not eligible for the study will have the reasons for ineligibility recorded 
within a screening log. Individuals who express their interest in attending the initial screening 
clinic appointment will receive one reminder letter and a telephone call to confirm that they 
wish to participate in the trial, and will be able to rearrange the screening appointment, if 
needed.  
 
 

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A screening hub will be established. The screening visit and imaging studies will be held on 
a single day or split across more than one-day dependent on participant preference and 
availability of clinic and MRI time. 
At the clinical screening appointment, the inclusion and exclusion criteria will be verified and 
eligible patients who wish to proceed will then provide informed written consent and will be 
enrolled in the study. Written informed consent will be obtained before any further 
procedures are undertaken and only once the potential participant is satisfied that all their 
questions have been addressed. A trained member of staff will obtain written informed 
consent and a unique study number will be assigned to the participant. The original signed 
consent form will be filed in the investigator’s site file and a copy given to the participant. 
The baseline visit case report form (CRF) and baseline assessment will be completed and 
signed by the investigator as outlined in section 6.1. The participant is then deemed as being 
registered into the study and the GP will be informed. 
 
 
 
 
 

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Figure 2: Recruitment flow chart 
GP Practices invited to express an interest in 
PROSTAGRAM (via CRN) 
GP practice expression of interest gained 
GP practice agrees to participate in PROSTAGRAM 
Postal Recruitment: 
The practices produce a list of 
eligible patients. Invitation letters 
and short information sheet sent 
using DocMail 
Opportunistic Recruitment: 
GP gives information pack to 
interested eligible individual 
during routine consultation for 
other medical issues 
Supplementary Recruitment: 
Individual contacts study team 
directly (e.g. online surveys, 
newspaper adverts)   
Expression of interest 
received by study team 
Further reminder and  
Non-response questionnaire 
No further contact. 
Telephone Discussion 
- Informative telephone conversation 
with member of study team 
- Inclusion/exclusion criteria check list 
Ineligible 
Do not continue with full enrolment. 
Record reason for ineligibility. 
Provide PSA screening advice 
PIS & Consent Form sent by post/email 
Screening Clinic 
- Re-check Eligibility. PIS discussion. 
Informed consent & Enrolment 
No response 
After 2 weeks 
Declines 
Do not continue with full enrolment.  
Reasons for declined entered into 
recruitment log 
No response 

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5.3.1 Randomisation of Biopsy Lesion 
 
If both the MRI and ultrasound are scored as suspicious by the relevant scoring system, 
these men will be randomised to have their ultrasound or MRI targeted biopsies first in order 
to reduce incorporation bias. This can occur as the biopsy tracts from the first lesion may 
influence the tracts of the second lesion.   
Therefore, a pseudo-randomisation will be carried out by a random number generator in 
advance of the trial starting. Block randomization will be employed to keep the numbers in 
each group as similar as possible. A block size of 4 has been chosen to reduce the chances 
that the biopsy order is inadvertently guessed by the operators. Allocation will be held by 
the Imperial Clinical Trials Unit and the order for lesions to be biopsied passed to the 
operating surgeon before the procedure begins. No provision for out-of-hours randomization 
will be required for this study of elective procedures. Occasional audit of the demographic 
and other characteristics of the groups produced during the study will ensure a balance 
between the two groups. 
5.3.2 Randomisation of screening tests 
In order to allow to limit reporter/reviewer bias all screening test will be interpreted by an 
independent assessor blinded to the results of the other tests. In particular, the MRI and US 
report will be issued prospectively prior to any prostate biopsy. The pathologist will be 
blinded to the results of imaging/PSA. 
It is not practical to fully blind the biopsy surgeon to the results of the screening tests, as the 
procedure will vary dependent on whether there is a lesion on the image-screening test. 
Therefore, the study team will inform the biopsy surgeon whether targeting needs to be 
incorporated into the biopsy strategy and the location of any areas suspicious on imaging.  
This need for biopsy also means that it will not be feasible to fully blind participants to their 
screening result. However, if participants are informed of all their results this a potential 
source of attrition bias if participants selectively withdraw from undergoing biopsy based on 
the results of a single test. Participants may place undue emphasis on the image based 
screening tests at the expense of the PSA or biomarker test. To reduce the risk of selective 
withdrawal men who are recommended for biopsy will be informed that one or more of their 
screening test is positive. However, the specific test indicating a biopsy will not be made 
available to participants until after the prostate biopsy.  Men who have a complete set of 
negative screening tests will be informed that no biopsy is required. 
Men will be unblinded to the screening test results after having a biopsy or on exiting the 
trial due to negative screening tests.  If a participant withdraws from the trial, they will be 
unblinded to their screening test result. There should be no other reasons for unblinding 
during the study. 
 

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The table below includes the recommended schedule of events.   
 
 
RECRUITMENT 
 
Screening 
Visit 
FOLLOW UP 
 
Invitation 
Telephone 
screening 
Biopsy 
Visit 
Final Visit 
(primary end 
point) 
Long 
Term 
Follow up 
Invitation, and flyer 
x 
 
 
 
 
 
Screen for 
eligibility 
 
x 
 
 
 
 
Explain screening 
procedures 
 
x 
 
 
 
 
Informed consent  
 
 
x 
 
 
 
Demographics, 
medical history, 
concomitant meds, 
clinical assessment  
 
 
x 
 
 
 
Physical 
examination and 
DRE 
 
 
x 
 
 
 
Questionnaires 
(SF-12, STAI, 
CWS) 
 
 
x 
x 
x 
 
PSA 
 
 
x 
 
 
 
MRI 
 
 
x 
 
 
 
Ultrasound 
 
 
x 
 
 
 
Acceptability 
questionnaires 
 
 
x 
 
 
 
Episwitch and 
biobank samples 
(optional) 
 
 
x 
 
 
 
Prostate Biopsy  
 
 
 
x 
 
 
Adverse Event 
assessments and 
subject compliance 
 
 
x 
x 
x 
 
Resource 
utilisation data 
 
 
 
 
x 
 
Long term follow 
up data (optional) 
 
 
 
 
 
x 
 
 

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Linkage to National databases  
The recruitment period will end once 366 (406 with dropouts) participants have been entered 
into the study, and the last participant has attended the screening clinic. The recruitment 
period is expected to last 24 months.  The follow-up phase of the study will be complete 
when the last patient has had their final follow-up visit, which should take place 
approximately one month after any biopsy procedure.  
The long-term outcomes of the PROSTAGRAM cohort will be important for evaluating any 
effect on survival of this group.  
The study will include optional consent to allow the use of patient identifiers to link our 
patients to national databases so that we might derive long-term outcomes in future if further 
downstream funding is gained to do this. We do not transfer any new data to these existing 
national databases.  This allows the potential to determine the rates of interval prostate 
cancers. The term interval cancer denotes a cancer diagnosed after a negative screening 
examination. The rate of interval cancers arising following a screening test is an important 
performance indicator for a population based screening test.  
  
Collection of partial postcodes  
In order to get an area-based estimate of deprivation, the participants’ partial postcodes will 
be converted into an Index of Multiple Deprivation (IMD) score. The IMD is the established 
index of deprivation for England Wales and has been adopted widely in studies across local 
and national government. Partial postcodes will not be stored in the InForm Database only 
IMD rank, which is based on detailed ward-level index of deprivation based on severe 
separate domains.  
 
 
 
5.6.1 Urinalysis 
Urinalysis will be performed locally to evaluate for evidence of urinary tract infection.  
The urine samples will be stored for 7 days post analysis and then auto disposed in tiger 
stripe (offensive waste) bag as per the Trust Clinical Waste Management Policy.  
The urine samples might be collected and stored for Biobanking and may in future undergo 
further analysis if new biomarkers are discovered that may be of clinical use in diagnosing 
prostate cancer (optional consent). Urine samples for biobanking will be stored in -80’ C 
freezers within approved biobank facilities at Imperial College Healthcare Tissue Bank for a 
period of 10 years.  
 
 

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5.6.2 PSA 
Collection of five millilitres of blood via peripheral venepuncture and place in a plastic tube 
containing SST (serum separating tube). This will be processed in a local laboratory.  
The blood samples will be stored for 4 days post analysis and then auto disposed to bio-
bins and incinerated off site according to the Trust Clinical Waste Management Policy.  
The blood samples might be collected and stored for Biobanking and may in future undergo 
further analysis if new biomarkers are discovered that may be of clinical use in diagnosing 
prostate cancer (optional consent). Blood samples for biobanking will be stored in -80’ C 
freezers within approved biobank facilities at Imperial College Healthcare Tissue Bank for a 
period of 10 years.  
 
 
5.6.3 Episwitch biomarker panel 
Collect six millilitres of blood via peripheral venepuncture using a 22 gauge or larger bore 
needle and place in a plastic tube containing EDTA (for options see below). 
The tube filled with blood is then thoroughly mixed by repeated gentle inversion between 10 
to 12 times immediately after collection. The mixed blood should be placed in a –20 to - 
80oC freezer within 60 minutes of collection and stored at that temperature until shipping. 
This is an optional test.  
 
The Episwitch biomarker panel will be stored within the biobank facilities. Shipments of 
samples in groups of 100 to be provided to Oxford Biodynamics (OBD) ISO-certified (9001) 
Processing Reference Facility in full accordance with OBS HTA license and Quality 
Management System. Address: Reference Laboratory (UK): First Floor, Building 7600 C2, 
The Quorum, Oxford Business Park North, Garsington. These samples will be identifiable 
only by anonymised study ID. The company will not receive any study related data and will 
not be involved in outcome analysis. The contractual agreement is that they only provide an 
analysis of anonymised samples for the study.  
Samples sent for Episwitch biomarker testing will be destroyed at the end of the study in 
accordance with the Human Tissue Authority's Code of Practice and Oxford Biodynamics 
Clinical Waste Management Policy.  
 
 
 
 
 
 

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6. INTERVENTION (IF APPLICABLE) 
 
 
After obtaining informed consent and registering the patient in the study the following 
clinical and baseline assessments will be undertaken: 
 A clinical history and review of concomitant medications. 
 Specific history related to family history of prostate cancer and urinary symptoms. 
 Ethnicity will be recorded.  
 Physical examination including digital rectal examination (DRE) 
 IPSS, SF-12, CWS and STAI questionnaire 
 
 
 
 
The participant will undergo venous blood sampling for: 
 PSA - collected prior to rectal exam.  
 Biobanking of urine/blood  
 Episwitch biomarker panel  
The specific collection procedures for each these samples are detailed in a Standard 
Operating Procedure (SOP Serum and Urine Samples).  
 
 
All men will undergo a screening prostate MRI. It is not necessary for participants to have a 
renal function performed prior to MRI as the scan is performed without contrast. Specifics of 
MRI protocol, sequences and reporting employed will be detailed in a Standard Operating 
Procedure (SOP MRI). An antispasmodic agent such as Hyoscine butylbromide should be 
administered prior to the scan. If there are contra indication then Glucagon can be 
administered. The presence of a discrete radiological score 3, 4 or 5 lesion recorded by 
radiologist or a lesion on CAD/AI leads to a targeted biopsy. All MRIs will be reported by 
experienced uro-radiologists who are compliant with the standards laid down by the British 
Society of Uro-Radiology (BSUR).   
 
 
Participants will be offered to undergo an ultrasound prior to MRI. The technique for image 
acquisition and reporting will be standardised in a Standard Operating Procedure (SOP MP-
USS). Participants who have identified prostate lesions on ultrasound scored as 3 or greater 
by the relevant scoring system will be offered a prostate biopsy. 
 

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Participants will complete the following validated questionnaires during the study in 
additional to questionnaires at baseline 
1. SF-12 
It consists of 36 items to derive eight profiles of functional health and well-being.  
This will be completed at baseline (T0), following receiving test results (T1) and in 
those with a positive test requiring a biopsy after the biopsy result (T2) 
 
 
 
2. The Spielberger state-trait anxiety inventory(STAI)  
This has been widely used to evaluate the impact of the screening process on 
healthy participants. It is designed to assess the changes in transitory anxiety such 
as might be experienced in a screening programme. 
This will be completed at baseline (T0), following receiving test results (T1) and in 
those with a positive test requiring a biopsy after the biopsy result (T2) 
 
3. The Cancer Worry Scale (CWS) 
The CWS was originally created to assess breast cancer worry and has been 
adapted for other malignancies including colon and prostate cancer. The revised 
CWS scale consists of three questions, one question regarding the frequency of 
cancer worry and two questions regarding the impact of worry about prostate 
cancer on mood, and daily functioning, respectively.  
This will be completed at baseline (T0), following receiving test results (T1) and in 
those with a positive test requiring a biopsy after the biopsy result (T2) 
 
4. Modified Expected burden questionnaire (EBQ) and perceived bur-den 
questionnaire (PBQ) 
The EBQ and PBQ evaluate information on the expected embarrassment, pain and 
burden of a diagnostic test. They have been validated in FOBT and CT colonoscopy 
screening and modified for this population. The EBQ will be completed prior to each 
test and the PBQ following each test.  
 
 
Men will proceed to biopsy if any screening test is positive. This includes 
 PSA: A raised PSA is defined as PSA ≥ 3.0ng/ml as per UK screening guidelines  
 MRI: The presence of a discrete radiological score 3, 4 or 5 as scored by a 
radiologist or lesion on CAD/AI  
 Ultrasound: The presence of prostate lesions on ultrasound 
If there is a lesion detected on an image based screening test men will have image-fusion 
guided biopsies for each lesion detected under local anaesthetic or sedation. The targeted 

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biopsy procedure will follow a Standard Operating Procedure (SOP Prostate Biopsies). Men 
will have been randomised by means of random number generator result to have either their 
MRI or ultrasound derived lesions biopsies first in order to overcome incorporation bias 
affecting the biopsy procedure.  
If no lesion is identified, men will have a systematic prostate biopsy as per the local centre 
standard of care pathway.  Prostate biopsy tissues samples will be preserved in formalin as 
soon as they are taken. All biopsy samples will be transported to Imperial College Healthcare 
NHS Trust for processing. No additional samples will be taken beyond what is required for 
a clinical diagnosis as outlined in the biopsy SOP.  
The prostate biopsy samples will be stored in Imperial College Healthcare NHS Trust 
pathology department for a period of 30 years of and destroyed as per the standard 
operating regulations of the NHS laboratories.  
The prostate biopsy samples will be stored in Imperial College Healthcare NHS Trust 
pathology department for a period of 30 years of and destroyed as per the standard 
operating regulations of the NHS laboratories.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7. SAFETY REPORTING  
 
Safety parameters will include the following:  
1. Urinalysis: Testing for both nitrite and leukocyte esterase as indicators of 
bacteriuria  
2. Blood tests for PSA: Values outside the reference range will be flagged and the 
abnormal values will be presented 
3. The frequency and incidence of serious adverse events (SAE) occurring through 
the course of the study 
 
 
An AE is any untoward medical occurrence in a patient or clinical trial subject. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, whether or not considered related to the trial protocol.  
 
 
For the purposes of the study, AEs will be followed up according to local practice until the 
event has stabilised or resolved, or the Follow-up Visit, whichever is the sooner. Serious 
adverse Events (SAE) will be recorded throughout the study. 
 
7.4 Severity of Adverse Events  
Mild:  
Awareness of event but easily tolerated 
Moderate: Discomfort enough to cause some interference with usual activity 
Severe: 
Inability to carry out usual activity 
 
 
 
Unrelated: 
 
No evidence of any causal relationship 
 
Unlikely: 
 
There is little evidence to suggest there is a causal relationship (e.g. the 
event did not occur within a reasonable time after a study procedure). 
There is another reasonable explanation for the event (e.g. the patient’s 
clinical condition, other concomitant treatment). 
 
Possible: 
There is some evidence to suggest a causal relationship (e.g. because 
the event occurs within a reasonable time after conducting a study 
procedure). However, the influence of other factors may have 
contributed to the event (e.g. the patient’s clinical condition, other 
concomitant treatments). 

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Probable: 
There is evidence to suggest a causal relationship and the influence of 
 
 
 
other factors is unlikely. 
 
Definite: 
 There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
 
 
 
7.6.1 Definition of SAE 
An SAE is defined as any event that  
 Results in death;  
 Is life-threatening*; 
 Requires hospitalisation or prolongation of existing inpatient’s hospitalisation**; 
 Results in persistent or significant disability or incapacity; 
 Is a congenital abnormality or birth defect; 
 
* “Life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
** “Hospitalisation” means any unexpected admission to a hospital department. It 
does not usually apply to scheduled admissions that were planned before study 
inclusion or visits to casualty (without admission).  
 
Medical judgement should be exercised in deciding whether an adverse 
event/reaction is serious in other situations. Important adverse events/reactions that 
are not immediately life threatening, or do not result in death or hospitalisation but 
may jeopardise a subject, or may require intervention to prevent one of the other 
outcomes listed in the definition above should also be considered serious. 
 
 
The following AEs that could be reasonably expected during the course of the study for 
each procedure.  
Expected Adverse Events Associated with Venepuncture Procedure 
 
 Haematomas and ecchymoses around venepuncture site  
 Minor discomfort 
 Infection 

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The following Adverse Events are associated with MRI:  
 Claustrophobia 
 Anxiety/Stress  
 Discomfort 
Note: No contrast agent is used in the study prostate MRI protocol 
The MRI is a non-contrast scan and equipped with monitoring methods that allow 
conversation with the participants and identification of any anxiety or discomfort. A detailed 
history for absolute and relative contraindications for a non-contrast MRI will be taken as set 
out in MRI SOP.  
 
 
Minimal rectal discomfort during the procedure 
An antispasmodic agent such as Hyoscine butylbromide should be administered prior to the 
scan. If there are contra-indication then glucagon maybe used. These are standard 
injections used during MRI scans. Side effects include blurred vision, dry mouth, dizziness, 
increased heart rate, constipation and pain at the injection site.  
 
 
The expected risks of the biopsy procedure include: 
 Blood in the urine (Haematuria) is common for up to 48 hours 
 Pain passing urine (Dysuria) is common for up to 24 hours 
 Blood in the semen is common (Haematospermia) for up to 3-4 months 
 Temporary pain/discomfort in the perineal area 
 Temporary problems with erections for up to 6-8 weeks (less than 1 in 20, <4-6 
weeks) 
 Retention of urine requiring a temporary catheter (1 in 100) 
 Prostatitis (inflammation or infection of the prostate (1 in 100)  
 Infection requiring admission and intravenous antibiotics (0.5-4%) 
The majority of biopsies will be performed under local anaesthetic and/or sedation. A small 
proportion might be offered a general anaesthetic for technical reasons and patient 
preference as per local standard practice. The expected risks from undergoing the local 
anaesthetic and conscious sedation procedure include: 
 Nausea and vomiting (1 in 10). 
 Minor bruises from intravenous catheters (drips) are common. 
 Occasionally extensive bruising, temporary hardening of the vein (phlebitis) or 
infection can occur from intravenous catheters (1 in 20).    
 Dizziness/Vertigo 

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 Confusion/Disorientation 
 Respiratory depression and apnoea (rare) 
 Anaphylaxis to Local Anaesthetic (1 in 200 000) 
There are expected risks associated with the procedure under general anaesthetic including: 
 Nausea and vomiting (1 in 10).  
 Most men will have a dry cough for an hour or two and may experience a sore 
throat for 24 hours.  This occurs because a mask and /or tube are placed in the 
throat during the anaesthetic. 
 Minor bruises from intravenous catheters (drips) are common. 
 Occasionally extensive bruising, temporary hardening of the vein (phlebitis) or 
infection can occur from intravenous catheters (1 in 20).    
 Death. The known risk of death under anaesthesia in the UK is 1 in 150,000 
anaesthetics. 
 
 
 
Rapid reporting of all SAEs i.e. within 24 hours, occurring during the study must be 
performed as detailed in SAE reporting instructions. If the investigator becomes aware 
of safety information that appears to be related to the trial, involving a subject who 
participated in the study, even after an individual subject has completed the study, this 
should be reported to the Sponsor. 
 
All SAEs will be reviewed by the Chief Investigator or a designated medically qualified 
representative to confirm expectedness and causality. 
 
Reporting of SAEs and review by the CI will be via the trial data collection system 
(CRF/eCRF).  
 
 
 
Related: resulted from administration of any of the research procedures 
 
 
 
 
Unexpected: type of event is not listed in the protocol as an expected occurrence 
 
 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours. 
However, relapse, death and/or hospitalisations for elective treatment of a pre-existing 
condition do not need reporting as SAEs.  

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All SAEs should be reported to the relevant REC where in the opinion of the Chief 
Investigator, the event was:  
 ‘Related’, i.e. resulted from the administration of any of the research procedures; and  
 ‘Unexpected’, i.e. an event that is not listed in the protocol as an expected occurrence  
Reports of related and unexpected SAEs should be submitted within 15 days of the 
Chief Investigator becoming aware of the event, using the NRES SAE form for non-IMP 
studies. The Chief Investigator must also notify the Sponsor of all SAEs. Local 
investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs are as follows:  
 
Joint Research Compliance Office  
Imperial College London and Imperial College Healthcare NHS Trust  
E-mail: jrco@imperial.ac.uk 
 
Chief Investigator  
Professor Hashim Uddin Ahmed  
Imperial College London, Charing Cross Campus  
E-mail: hashim.ahmed@imperial.ac.uk 
Tel: 
0 20 7589 5111 (Mon to Fri 09.00 – 17.00) 
 
 
 
Annual Progress reports will be submitted to the Research Ethics Committee and the 
Sponsor in accordance with local requirements. The annual Progress report will detail all 
SAE recorded.  
 
 
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any 
event no later than 3 days from the date the measures are taken, give written notice to 
the relevant REC of the measures taken and the circumstances giving rise to those 
measures. 
 
8. DISCONTINUATION & WITHDRAWAL FROM STUDY 
 
The Sponsor may terminate the study at any time if the following occur, and the 
investigator is unable to take corrective action in any of these cases: 
 The investigator is non-compliant with the protocol 
 The investigator is non-compliant with the regulatory requirements 

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 The investigator is non-compliant with the principles of Good Clinical Practice as  
outlined in the Declaration of Helsinki and the Research Governance Framework 
 The CRF completion is inadequate  
 
 
If an unwanted effect is considered severe by the Chief Investigator and endangers  the 
health of all patients, the study will be discontinued after agreement with the  Sponsor.  
 
 
 
The criteria for discontinuing the study in the case on individual patients are: 
 Intercurrent illness: Any illness, which in the judgment of the investigators would 
affect the assessments of clinical status to a significant degree 
 Request by the patient: It is the patients right to request discontinuation of their 
participation in the study. If this request is made, it will be respected and will not 
affect the patient’s ability to receive medical care from the investigators now or 
in the future.  
 Discontinuation of attendance at the investigating site: Efforts should be made 
to maintain the investigations schedule and continue follow-up, even if patients 
no longer attend the participating institution. 
 
 
Withdrawal from the study refers to discontinuation of study intervention and study 
procedures and can occur for the following reasons: 
 Participant decision 
 Inability to conduct any one of the imaging tests, blood tests or biopsies according 
to protocol.  
 Loss to follow-up 
 
8.4.1 Procedures for Withdrawal from Study 
Each participant has the right to withdraw from the study at any time. Withdrawal may 
be complete (i.e. from further study procedures and any follow up), or partial (e.g. from 
study procedures but allowing the possibility of further follow up). All communication 
surrounding the withdrawal should be noted in the patient’s records, and where 
withdrawal is complete, no further CRFs should be completed for that patient. Data up 
to the time of withdrawal can be included in the study if anonymised. 
Participants who withdraw will be replaced to maintain the accrual of patients. 
All participants who withdraw will remain eligible for follow-up via standard of care 
prostate cancer screening which is available through informed discussion of the risks 
and benefits with their GP.  

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9. STATISTICAL ANALYSES 
 
The study is powered for the primary objective to determine the prevalence of screen-
positive MRIs in the general male population aged 50-69 years. We have followed the 
formula recommended by Naing et al(46) to determine an adequate sample size to 
estimate the prevalence of screen positive MRIs with a precision of +/- 5% 
 
 
Z = Z statistics for a level of confidence 
P = expected prevalence or proportion 
d = precision. 
The sample size calculation requires an estimate of the prevalence of screen-positive 
MRI (p). There are no previous studies that provide a reliable estimate of this figure in 
50-69 years at average risk of prostate cancer. We have estimated this figure based on 
a number of assumptions, which are listed below. We have split the population into 2 
groups depending on PSA level, as there are different levels of evidence for each group.  
GROUP 1: PSA raised (PSA ≥ 3.0): 
We have assumed this to be 73% based on a combination of studies. 
 The PROMIS study has shown that in a group of biopsy-naïve men referred with 
a suspicion of prostate cancer, the prevalence of positive MRI (Likert ≥ 3) was 
72.6%(7). 
 The PRECISION study which used PI-RADS v2 and found a prevalence of 71.1% 
(47) for PIRADS ≥ 3. 
 A recent review, which did not include PROMIS and PRECISION, categorising PI-
RADS threshold across different groups of men confirmed that 73% of biopsy-
naïve men have a positive scan defined as PI-RADS score(48).  
 
GROUP 2: PSA normal (PSA ≤ 3.0): 
There is limited data on the number of positive MRIs in this group so we have combined 
previous research estimating 
1. The prevalence of expected significant cancers 
2. The performance characteristics of MRI: 
 
1. The prevalence of clinically significant disease in men with normal PSA 
In the Prostate Cancer Prevention Trial (PCPT), this estimated that the prevalence of 
clinically significant disease in a normal PSA population is 2.20% (49, 50). The reference 
test was a 6-core (sextant) biopsy, which is known to underestimate the presence of cancer 

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and has been replaced with a 10-12 core approach. However, we do not have any reference 
to estimate by how much the 6-core biopsy underestimates the clinically significant disease 
in a normal PSA population. Therefore, we hypothesise that the prevalence of undiagnosed 
clinically significant disease in this group is 2.20%. 
 
 
2. The performance characteristics of MRI:  
a. We will assume that the performance characteristics (sensitivity and specificity) 
of mp-MRI to detect clinically significant disease  are the same in a normal  and 
raised PSA population.  
b. These performance characteristics are variable across the literature.  
i. A meta-analysis by Rooij et al 2014(51) reported a sensitivity and 
specificity of 74% and 88% respectively. 
ii. The recent PROMIS study(7) (not included in Rooij et al) reported a 
sensitivity and specificity of 93% and 41% respectively. 
c. We have calculated the assumed prevalence of a positive MRI in a normal PSA 
population using both these performance characteristics using the following 2x2 
table. 
 
 
Clinically significant 
prostate cancer 
             MRI 
 
Diseased Non- 
diseased 
Total 
Positive 
a 
b 
P Normal 
PSA 
Negative 
c 
d 
 
Total  
2.20% 
97.80% 
 
 
d. Based on the performance characteristics in Rooij et al 2014: 
i. Sensitivity: 74% 
a/ (a+c) = 0.74 
a/0.022 = 0.74 
 
a = 0.0163 c = 0.0057  
 
ii. Specificity: 88% 
d/(b+d) = 0.88 
d/0.978 = 0.88  
b = 0.1174 
d = 0.8606 
 
 

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ROOIJ ET AL 
2014 
Clinically significant  
prostate cancer 
            MRI 
 
 Diseased 
Non- 
diseased Total 
Positive 
1.63% 
11.74% 
 13.37% 
Negative 
0.57% 
86.06% 
86.63% 
Total  
2.20% 
97.80% 
 
 
 
Based on the performance characteristics in Ahmed et al 2017: 
iii. Sensitivity: 93% 
a/(a+c) = 0.93 
a/0.022 = 0.93  
a = 0.0205 
c = 0.0015 
 
iv. Specificity: 41% 
d/(b+d) = 0.41 
d/0.978 = 0.41 
b = 0.5770 
d = 0.4010   
 
AHMED 
ET 
AL 2017 
Clinically significant  
prostate cancer 
MRI 
 
Diseased 
Non- 
diseased 
Total 
Positive 
2.05% 
57.70% 
59.75% 
Negative 
0.15% 
40.10% 
40.25% 
Total  
2.20% 
97.80% 
 
 
 
e. Therefore given these performance characteristics the prevalence of a positive 
MRI in a normal PSA population will be either 
i.  13.37% based on Rooij et al 2014(51) 
ii. 59.75% based on Ahmed et al 2017 (7). 

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The final part of the calculation is to combine the assumed prevalence of positive MRI in the 
normal and raised PSA groups to estimate the prevalence of  positive MRI in a mixed 
population. There is high quality evidence for the expected percentage of normal and raised 
PSA from the Cluster randomised trial of PSA testing for Prostate cancer (CAP)(52), 
namely:- 
 Raised PSA: 10.4%  
 Normal PSA: 89.6%.  
Therefore, using our estimates above for the prevalence of positive MRIs in a normal PSA 
population, we expect 11.98% (13.37% of 89.6%) (Rooij  et al) and 53.54% (59.75% of 
89.6%) (Ahmed et al). The positive prevalence in a raised PSA population is 7.59% (73% of 
10.4%). 
This produces an assumed prevalence of positive MRI in both groups of 19.6% (Rooij  et al) 
or 61.1% (Ahmed et al). Based on 95% confidence interval (z = 1.96) and precision (d) 0.05, 
these sample sizes can be represented on the below graph at different prevalence 
estimates.  
 
 
Using the formula by Naing et al. (46), assuming a prevalence of  19.6% requires a sample 
size of  243 participants. While assuming a prevalence of  61.1% will require a sample size 
of 366 participants. Allowing for a 10% dropout this requires a sample size of  270 and  406 
participants respectively. 
 
100
200
300
400
500
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
60%
Number of MRI (n)
Estimated prevalence (p)
19.6% 
243 
61.1% 
366 

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The estimated postal response rate is 10-20% based on the experience of the CAP study. 
Given an expected 10% response rate, we will need to post 4,800 letters to reach 
recruitment targets with postal recruitment alone. It is unknown the recruitment rates for 
opportunistic and other forms of recruitment. The recruitment rates will be monitored to 
ensure a stable recruitment rate given MRI and biopsy capacity.  
 
 
A statistical analysis plan will be prepared and finalised prior to database lock.  
 
 
 
 
 
 
 

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10. REGULATORY, ETHICAL AND LEGAL ISSUES 
 
The investigator will ensure that this study is conducted in full conformity with the seventh 
revision of the 1964 Declaration of Helsinki. 
 
 
The study will be conducted in accordance with the guidelines laid down by the International 
Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 guidelines).  
 
 
 
10.3.1 Initial Approval 
Prior to the enrolment of subjects, the REC must provide written approval of the conduct of 
the study at named sites, the protocol and any amendments, the Subject Information Sheet 
and Consent Form, any other written information that will be provided to the subjects, any 
advertisements that will be used and details of any subject compensation.  
 
 
10.3.2 Approval of Amendments 
 
Proposed amendments to the protocol and aforementioned documents must be submitted 
to the REC for approval as instructed by the Sponsor. Amendments requiring REC approval 
may be implemented only after a copy of the REC’s approval letter has been obtained.  
 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may 
be implemented prior to receiving Sponsor or REC approval. However, in this case, approval 
must be obtained as soon as possible after implementation. 
 
 
 
The REC will be sent annual progress reports in accordance with national requirements. 
 
 
The REC will be sent Annual Progress updates in order to facilitate their continuing review 
of the study (reference. ICH GCP E6 Section 3.1.4) and will be informed about the end of 
the trial, within the required timelines. The Annual Progress Report will detail all SAEs 
recorded.  

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Health Research Authority (HRA) approval will be obtained prior to starting the study. Each 
participating site will confirm capacity and capability prior to commencing. 
The HRA and all participating sites also need to be notified of all protocol amendments to 
assess whether the amendment affects the institutional approval for each site.  
 
 
None required as no ionising radiation or administration of radioactive substances are 
required in the protocol. 
 
 
All protocol deviations and protocol violations will be reported via the eCRF/CRF and 
reviewed by the Chief Investigator and reported to the ICTU QA Manager on a monthly 
basis. Protocol violations will be reported to the Sponsor. 
An assessment of whether the protocol deviation/violation constitutes a serious breach will 
be made.  
A serious breach is defined as: 
A breach of the conditions and principles of GCP in connection with a trial or the trial 
protocol, which is likely to affect to a significant degree:  
 The safety or physical or mental integrity of the UK trial subjects; or 
 The overall scientific value of the trial 
 
The Sponsor will be notified within 24 hours of identifying a likely Serious Breach. If a 
decision is made that the incident constitutes a Serious Breach, this will be reported to the 
REC within 7 days of becoming aware of the serious breach. 
 
 
 
Imperial College London holds negligent harm and non-negligent harm insurance policies, 
which apply to this study. Imperial College London will act as the main Sponsor for this 
study.  Delegated responsibilities will be assigned to the NHS trusts taking part in this study.  
 
 
The study will be registered on an International Standard Randomised Controlled Trial 
Number (ISRCTN) database in accordance with requirements of the International 
Committee of Medical Journal Editors (ICMJE) regulations.  
 
 

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Subjects should be provided with a copy of the signed Subject Information Sheet/Informed 
Consent Form document. The original Informed Consent Form should be retained with the 
source documents. 
 
 
 
It is the investigator’s responsibility to inform the subject’s General Practitioner (where 
applicable) by letter that the subject is taking part in the study provided the subject agrees 
to this, and information to this effect is included in the Subject Information Sheet and 
Informed Consent. A copy of the letter should be filed in the medical notes.  
 
 
The investigator must ensure that the subject’s confidentiality is maintained. On the CRF or 
other documents submitted to the Sponsors, subjects will be identified by a subject ID 
number only. Documents that are not submitted to the Sponsor (e.g., signed informed 
consent form) should be kept in a strictly confidential file by the investigator. 
 
The investigator shall permit direct access to subjects’ records and source document for the 
purposes of monitoring, auditing, or inspection by the Sponsor, authorised representatives 
of the Sponsor, NHS and regulatory authorities. 
 
The investigator will preserve the confidentiality of all participants taking part in the study, 
which will be conducted in accordance with the Data Protection Act.  
 
 
The end of trial will be when all participants have completed their final follow-up visit (Visit 
3) or at the request of the Trial Steering Committee. The final visit should take place within 
approximately one month of the biopsy procedure. 
During this final visit, the study team will discuss the results of all screening study tests and 
biopsy results with the patient. Any side effects of the tests experienced by the patient can 
be discussed. This consultation marks the end of the study for participants. 
 
 
 
The study investigators and study site staff will comply with the requirements of the Data 
Protection Act 2018 concerning the collection, storage, processing and disclosure of 
personal information and will uphold the Act’s core principles.  
 

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All research documentation and information will undergo a process of pseudonymisation 
where possible. Whilst within the study, patients will be identified by a unique study number, 
and the data in the CRF will be linked to this number. Research data will be entered onto a 
dedicated, secure, encrypted trial database, specifically constructed for the purpose. The 
study team will maintain the confidentiality of all patient data and will not disclose information 
by which patients may be identified to any third party other than those directly involved in 
the treatment of the patient and organisations for which the patient has given explicit consent 
for data transfer. Data within the NHS system such as patient notes, MRI reports and 
histopathology reports will remain confidential in accordance with NHS confidentiality code 
of practice.  
Paper enrolment logs, including patients’ names, NHS numbers and dates of birth, will be 
kept in the Investigator Site File, stored in a secure, code-locked store room within the 
designated Imperial College London facilities. Electronic enrolment logs will be kept on the 
Trust Computers stored in a locked office space within Imperial College London and Imperial 
College Healthcare NHS Trust premises. Access to these documents will be highly restricted 
and only be available to the relevant study team members.  
 
Contact details  
 
Contact details collected using online survey providers, will be encrypted during transit and 
at rest. All data collected from online surveys will be stored in the UK. Online survey used 
must remain fully compliant with GDPR legislation and European Privacy Laws. The list of 
online-responders will be exported to excel file and stored on Trust Computers. The GDPR 
transparency wording will be utilised to ensure online responders about their data being 
secured for a 2-year period and destroyed thereafter.  
 
MRI and US files  
 
All MRI will be stored in a secure and password-protected databank (XNAT: 
https://www.xnat.org/about/) held in Imperial College London Clinical Imaging Facility under 
university research governance protocols and standard operating procedures. All the US 
scans will be kept on the Ultrasound Machine used and backed-up onto an external hard-
drive on regular basis. The US machine and the external hard-drive will be kept at a code-
locked, secure room within Imperial College Clinical Imaging Facility.  
The anonymised MRI images will be transferred to a university computer/laptop to allow the 
AI/CAD reporting. This computer/laptop is encrypted and password protected using high 
levels of security in accordance with the University protocols. On completion of the study, 
this data will be transferred to the University servers and the laptop hard-drive wiped. 
 
 

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11. DATA MANAGEMENT 
 
 
Source documentation is defined as the first time data appear, and may include original 
document, data and records (hospital records, clinical reports, MRI and Ultrasound reports, 
other procedure reports, laboratory notes, other data recorded at the pathology and 
biochemistry laboratories, etc.). Information in source documents (e.g. medical history) 
dated prior to the Informed Consent Form signature date may be used to verify patient 
suitability for the study.   
Clinical records must be marked to indicate a subject has been enrolled into the clinical 
study.  
The Investigator must ensure the availability of source documents from which the 
information on the eCRF was obtained. Where printouts and electronic medical records are 
provided as source documents, they should be signed and dated by a member of the 
adequately trained research team, to indicate that the data provided is a true reproduction 
of the original source document.  
All study data may be inspected by sponsor and regulatory authorities by people working on 
behalf of the Sponsor, and by representatives of Regulatory Authorities, where it is relevant 
to this research.  
  
 
 
CRFs will be in English. Generic names for concomitant medications should be recorded in 
the CRF wherever possible. All written material to be used by subjects must use vocabulary 
that is clearly understood, and be in the language appropriate for the study site. 
 
 
 
The principal means of data collection from participant visits will be Electronic Data Capture 
(EDC) via the internet using the InForm database.  Data is entered into the EDC system via 
site personnel.  All source data recorded in the CRF will be signed by the Investigator or 
his/her appropriate designee.  All changes made following the electronic signing will have 
an electronic audit trail with a signature and date.  Specific instructions and further details 
will be outlined in the CRF manual.  
 
 
 

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All study data will be entered into electronic Case Report (eCRFs) in a database provided 
by the Sponsor (InForm). All eCRFs will be completed using de-identified data.  
CRF completion may be delegated by the Principal Investigator (documented on the 
Delegated Task List) to other study personnel u the Principal Investigator remains 
responsible for the accuracy and integrity of the  of all data entered to eCRFs.  
Further details of procedures for CRF/eCRF completion, including data review, database 
cleaning, issuing and resolving data queries, and identification of steps or creation, 
modification, maintenance and archiving of source data via any computerised systems will 
be provided in the study specific Data Management Plan (CRF manual).  
 
 
The investigator must retain essential documents until notified by the Sponsor, and for ten 
years after study completion. Subject files and other source data (including copies of 
protocols, CRFs, original reports of test results, correspondence, records of informed 
consent, and other documents pertaining to the conduct of the study) must be retained. 
Documents should be stored in such a way that they can be accessed/data retrieved later. 
Consideration should be given to security and environmental risks. 
 
No study document will be destroyed without prior written agreement between the Sponsor 
and the investigator. Should the investigator wish to assign the study records to another 
party or move them to another location, written agreement must be obtained from the 
Sponsor. 
 
Storage and handling of confidential trial data and documents will be in accordance with the 
Data Protection Act 2018 (UK) 
 
Contact details collected using online survey providers will be encrypted during transit and 
at rest. All data collected from online surveys will be stored in the UK. Online survey used 
must remain fully compliant with GDPR legislation and European Privacy Laws. 
 
The list of online-responders will be exported to excel file and stored on Trust Computers.  
Imperial College London will contact online responders about the research study, and make 
sure that relevant information about the study is recorded with care.  
  
The GDPR transparency wording will be utilised to ensure online responders about their 
contact details being secured for a 2-year period after study completion and destroyed 
thereafter.  
 

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12. STUDY MANAGEMENT STRUCTURE 
 
The role of the TSC is to provide overall supervision of trial conduct and progress. Details 
of membership, responsibilities and frequency of meetings will be defined in the TSC 
Charter. A TSC meeting will be held at the start of the trial prior to patient recruitment, and 
then annually as a minimum.  
  
 
The study team will meet regularly throughout the study to co-ordinate the project with other 
collaborators as deemed appropriate. When necessary, decisions will be referred to the 
TSC. Meetings will be scheduled in a risk-adapted manner to allow for the review of events 
during the trial. 
 
A study-specific risk assessment will be performed prior to the start of the study to assign a 
risk category of ‘low’, ‘medium’ or ‘high’ to the trial. Risk assessment will be carried out by 
the ICTU QA Manager in collaboration with the Study Manager and the result will be used 
to guide the Monitoring Plan. The risk assessment will consider all aspects of the study and 
will be updated as required during the course of the study. 
 
 
The study will be monitored periodically by trial monitors to assess the progress of the study, 
verify adherence to the protocol, ICH GCP E6 guidelines and other national/international 
requirements and to review the completeness, accuracy and consistency of the data. 
 
Monitoring procedures and requirements will be documented in a Monitoring Plan, in 
accordance with the risk assessment. 
 
Quality Control will be performed according to ICTU’s internal procedures. The study may 
be audited by a Quality Assurance representative of the Sponsor and/or ICTU. All necessary 
data and documents will be made available for inspection. 
The study may be subject to inspection and audit by regulatory bodies to ensure adherence 
to GCP and the NHS Research Governance Framework for Health and Social Care (2nd 
Edition).  
 
 
This study has been peer reviewed by the study funders; the Wellcome Trust and the 
Urology Foundation.  
 

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The results of the PROSTAGRAM trial will be submitted for publication in peer-reviewed 
scientific journals. Findings will be presented at relevant national and international scientific 
conferences. The work may also be included in theses and dissertations. Any submissions 
for publication using data from this study to undertake original analyses must have 
authorisation from the TSC.  
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. The 
investigator may use this information for the purposes of the study only. 
It is understood by the investigator that the Sponsor will use information developed in this 
clinical study and, therefore, may disclose it as required to other clinical investigators. In 
order to allow the use of the information derived from this clinical study, the investigator 
understands that he/she has an obligation to provide complete test results and all data 
developed during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 
Therefore, all information obtained as a result of the study will be regarded as 
CONFIDENTIAL, at least until appropriate analysis and review by the investigator(s) are 
completed.  
The results will be disseminated to participating GPs and to relevant organisations as their 
involvement will be critical in the subsequent larger studies. Participants who consent to 
receive a copy of the findings will receive a lay summary of the findings by post or email 
after the main report has been published  
Permission from the Executive/Writing Committee is necessary prior to disclosing any 
information relative to this study outside of the Trial Steering Committee. Any request by site 
investigators or other collaborators to access the study dataset must be formally reviewed 
by the TSC.    
The results may be published or presented by the investigator(s), but the Sponsor will be 
given the opportunity to review and comment on any such results for up to 1 month before 
any presentations or publications are produced. The funders’ terms and conditions do not 
require review of manuscripts or abstracts or posters prior to submission. 

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A Clinical Study Report summarising the study results will be prepared and submitted to the 
REC within a year of the end of study. 
 
 
There are expected to be a number of resulting publications and the authorship will be 
determined on a per paper basis by the Trial Management Group and Chief Investigator. All 
publications will acknowledge individual authors in accordance with normal academic 
practice. Individual authors are likely to include relevant members of the TSC listed 
individually or in the name of the ‘PROSTAGRAM Study Group’.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. REFERENCES 
1. 
Cancer 
Research 
UK. 
Prostate 
cancer 
statistics 
2014. 
Available 
from: 
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PROSTAGRAM 
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Imperial College London  
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PROSTAGRAM 
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Imperial College London  
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genitourinary cancer. 2017;15(4):429-39.e1. 
26. Kim EH, Andriole GL, Crawford ED, Sjoberg DD, Assel M, Vickers AJ, et al. Detection 
of High Grade Prostate Cancer among PLCO Participants Using a Prespecified 4-Kallikrein 
Marker Panel. The Journal of urology. 2017;197(4):1041-7. 
27. Nordstrom T, Vickers A, Assel M, Lilja H, Gronberg H, Eklund M. Comparison Between 
the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol. 
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28. Braun K, Sjoberg DD, Vickers AJ, Lilja H, Bjartell AS. A Four-kallikrein Panel Predicts 
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29. de la Calle C, Patil D, Wei JT, Scherr DS, Sokoll L, Chan DW, et al. Multicenter 
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PROSTAGRAM 
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Imperial College London  
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PROSTAGRAM 
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Imperial College London  
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   Version 1.2 01MAY2019 
 
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51. de Rooij M, Hamoen EHJ, Fütterer JJ, Barentsz JO, Rovers MM. Accuracy of 
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Oncology. 2014;15(10):1109-18. 
 
 
 
 
 

PROSTAGRAM 
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SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory and provides the 
necessary assurances that this study will be conducted according to all stipulations of the 
protocol including all statements regarding confidentiality. 
 
 
Study Title:  
 
PROSTAGRAM 
 
 
Protocol Number:  
18HH4595 
 
 
 
Signed:                                     
 
 
 
 
Professor Hashim Ahmed 
 
 
 
 
 
Date:      
  

PROSTAGRAM 
Protocol no: 
18HH4595  
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Imperial College London  
V 1.01MAY2019  
 
 
 
 
 
 
 
 
IRAS: 247728               Clinical Study Protocol           
   Version 1.2 01MAY2019 
 
66 of 67 
 
SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
PROSTAGRAM 
 
 
Protocol Number:  
18HH4595 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Becky Ward 
 
 
 
Research Governance Manager 
 
 
 
Imperial College London   
 
 
 
 
 
 
Date:  
 
 

PROSTAGRAM 
Protocol no: 
18HH4595  
Sponsor:  
Imperial College London  
V 1.01MAY2019  
 
 
 
 
 
 
 
 
IRAS: 247728               Clinical Study Protocol           
   Version 1.2 01MAY2019 
 
67 of 67 
 
SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
PROSTAGRAM 
 
 
Protocol Number:  
18HH4595 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Francesca Fiorentino 
 
 
 
Imperial College Trials Unit & Division of Surgery 
 
 
Date:  
 
_____________________ 
 
 
 
Study Title:  
 
PROSTAGRAM 
 
 
Protocol Number:  
18HH4595 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Ms Emily Day  
 
 
 
Imperial College Trials Unit & Division of Surgery  
 
Date:  
 
_____________________