PROState Pathway Embedded Comparative Trial
Conditions: Prostate Cancer, Non-metastatic Prostate Cancer, Metastatic Prostate Cancer, Prostate Adenocarcinoma, Metastatic Prostate Carcinoma in the Soft Tissue, Prostate Cancer Metastatic
Sponsor: Imperial College London

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
PROSPECT Protocol version 6.0 05 April 2022  
 
 
 
 
 
 
Page 1 of 71 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Full Study Title: 
 
PROState Pathway Embedded Comparative Trial  
 
Short Study title / Acronym: 
 
Imperial Prostate Study 3 
IP3-PROSPECT 
 
Product:   
 
 
 
 
 
N/A 
 
Development Phase:   
Phase II/III 
 
Sponsor:  
 
 
 
 
Imperial College London 
 
 
Version no:  
 
 
 
       6.0 
 
 
 
 
 
Protocol Date:   
 
 
5th April 2022 
 
 
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 
 
Research Reference numbers 
 
IRAS ID: 
272985 
REC Reference Number: 
20/LO/0459 
ISRCTN Number / Clinical trials.gov Number: 
ISRCTN11095538 / NCT04400656 
Sponsor Protocol Number: 
19CX5601 
Funder reference: 
204998/Z/16/Z 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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Page 2 of 71 
 
CONTACT LIST 
Chief Investigator 
 
Name: Professor Hashim U Ahmed 
Address: Room 5L28, 5th Floor, Laboratory Block, Charing Cross Hospital Campus, Imperial College 
London, Fulham Palace Road, London W6 8RF 
Tel: 
0203 311 1673 
Fax: N/A 
Email: hashim.ahmed@imperial.ac.uk 
  
 
Sponsor 
 
Sponsor’s Name: Imperial College London 
Address: Research Governance and Integrity Team (RGIT), Room 215, Level 2, Medical School 
Building, St Mary’s Campus, Norfolk Place, London W2 1PG 
 
Name of contact person: Ruth Nicholson 
Title: Head of Research Governance and Integrity  
Tel: 
Tel: 0207 594 1872 
Email: r.nicholson@imperial.ac.uk 
 
Funder 
 
Funder’s name: Wellcome Trust 
Address: Gibbs Building, 215 Euston Road, London, NW1 2BE, UK 
 
Clinical queries should be directed to the Clinical Trial Manger who will direct the query to the 
appropriate person: 
 
Clinical Trial Manager 
 
Name: Ms Puja Jadav 
Address: Imperial Prostate 
Division of Surgery, Charing Cross Hospital, 5L15, Laboratory Block, Fulham Palace Road, London, 
W6 8RP 
Tel: 0207 594 7271 | 0751 348 0679  
Email: p.jadav@imperial.ac.uk 
 
 
 
 
 
 
 
 
 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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Page 3 of 71 
 
ICTU Operations 
 
Name: Mrs Natalia Klimowska-Nassar  
Address: Imperial College Trials Unit & Division of Surgery 
1st Floor, Stadium House, 68 Wood Lane, London W12 7RH  
 
 
 
Tel: 0207 594 3424 
Email: n.klimowska@imperial.ac.uk  
 
 
Name: Dr Thiagarajah Sasikaran 
Address: Imperial College Trials Unit & Division of Surgery 
1st Floor, Stadium House, 68 Wood Lane, London W12 7RH  
 
 
 
Tel: 0207 594 6017 
Email: t.sasikaran@imperial.ac.uk 
 
 
Senior Statistician 
 
Name: Dr Francesca Fiorentino 
Address: Imperial College Trial Unit & Department of Surgery and Cancer 
Queen Elisabeth the Queen Mother Building (10th Floor/1091) St Mary’s Hospital 
Imperial College London, Praed Street, London, W2 1NY 
Tel: 0203 312 3761 
 
Co-Investigators 
 
Mr Edward Bass 
Clinical Coordinator  
Clinical Research Fellow and Specialist Trainee in Urology, Division of Surgery, Charing Cross Hospital, 
5L15, Laboratory Block, Fulham Palace Road, London, W6 8RP 
 
Mr Mathias Winkler 
Consultant Urological Surgeon 
Charing Cross Hospital 
Imperial College Healthcare NHS Trust 
Fulham Palace Road, London, W6 8RF 
Email : mathias.winkler@nhs.net 
 
 
ADMINISTRATIVE INFORMATION 
This document is a trial protocol describing IP3-PROSPECT, a study sponsored by Imperial 
College London, coordinated by ICTU-Surgery.  It provides information about procedures for 
entering participants into the trial, and provides sufficient detail to enable: an understanding 
of the background, rationale, objectives, trial population, intervention, methods, statistical 
analyses, ethical considerations, dissemination plans and administration of the trial; 
replication of key aspects of trial methods and conduct; and appraisal of the trial’s scientific 
and ethical rigour from the time of ethics approval through to dissemination of the results. 
The protocol should not be used as an aide-memoire or guide for the treatment of other 
patients. Every care has been taken in drafting this protocol, but corrections or amendments 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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Page 4 of 71 
 
may be necessary. These will be circulated to registered investigators in the trial.  Sites 
entering participants for the first time should confirm they have the correct version through 
a member of the trial management team. 
The study will be conducted in compliance with the approved protocol, the Declaration of 
Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission 
Directive 2005/28/EC with implementation in national legislation in the UK by Statutory 
Instrument 2004/1031 and subsequent amendments, the Human Tissue (Quality and Safety 
for Human Application) Regulations 2007, the UK Data Protection Act, and the National Health 
Service (NHS) UK Policy Framework for Health and Social Care . International sites will comply 
with the principles of GCP as laid down by ICH topic E6 (Note for Guidance on GCP), 
Commission Directive 2005/28/EC, the European Directive 2001/20/EC (where applicable), 
the EU Tissue and Cells Directives 2004/23/EC, 2006/17/EC and 2006/86/EC and other 
national and local applicable regulations. Agreements that include detailed roles and 
responsibilities will be in place between participating sites and Imperial College London. 
 
COMPLIANCE 
Participating sites will inform the trial management team as soon as they are aware of a 
possible serious breach of compliance, so that ICTU-Surgery can fulfil its requirement to 
report the breach if necessary within the timelines specified in the UK Clinical Trials 
Regulations (currently 7 days). For the purposes of this regulation a ‘serious breach’ is one 
that is likely to affect to a significant degree: 
• The safety or physical or mental integrity of the subjects in the trial, or 
• The scientific value of the trial. 
 
ABBREVIATIONS 
 
cmRCT 
Cohort Multiple Randomised Control Trial 
CRF 
Case Report Form 
CTA 
Clinical Trials Agreement 
ECOG 
Eastern Co-operative Oncology Group 
EQ5D-5L 
European Quality of Life Instrument (5 dimensions, 5 levels) 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form  
ICTU 
Imperial Clinical Trials Unit 
IIEF 
International Index of Erectile Function 
IPSS 
International Prostate Symptom Score 
mpMRI 
Multiparametric Magnetic Resonance Imaging 
NCRN 
National Cancer Research Network 
NHS 
National Health Service 
NHSCR 
National Health Service Care Register 
NIHR 
National Institute for Health Research 
PIS 
Participant Information Sheet 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
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PROMS 
Patient Reported Outcome Measures 
PSA 
Prostate Specific Antigen 
QoL 
Quality of Life 
RCT 
Randomised Control Trial 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Group 
TRUS 
Transrectal Ultrasound 
TWiCS 
Trials Within Cohorts 
USS 
Ultrasound 
 
KEYWORDS: 
 
prostate cancer; clinical trials; cohort multiple randomised control trial 
 
 
 
 
 
 
 
 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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Page 6 of 71 
 
Table of Contents 
CONTACT LIST ......................................................................................................................................... 2 
ABBREVIATIONS ...................................................................................................................................... 4 
TRIAL SUMMARY ..................................................................................................................................... 9 
Inclusion Criteria ................................................................................................................................... 10 
Patients ................................................................................................................................................. 10 
Exclusion Criteria................................................................................................................................... 10 
Patients ................................................................................................................................................. 10 
1. BACKGROUND ................................................................................................................................... 12 
1.1 SUMMARY ................................................................................................................................... 12 
1.2 RATIONALE FOR PROSPECT ......................................................................................................... 12 
1.3 TRIAL AIMS .................................................................................................................................. 17 
2. OBJECTIVES AND ENDPOINTS ........................................................................................................... 18 
3. STUDY DESIGN ................................................................................................................................... 20 
3.1 Design .......................................................................................................................................... 20 
3.2.1 POINT OF CONSENT ONE ............................................................................................................. 21 
3.2.2 POINT OF CONSENT TWO ............................................................................................................ 21 
3.4. AREAS TO BE INVESTIGATED BY PROSPECT ................................................................................... 24 
4. PARTICIPANT ENTRY .......................................................................................................................... 25 
4.1 STUDY SETTING AND POPULATION............................................................................................. 25 
5. PROCEDURES AND MEASUREMENTS ................................................................................................ 26 
5.1 IDENTIFICATION AND RECRUITMENT OF PATIENTS ................................................................... 26 
5.2 SCREENING EVALUATIONS .......................................................................................................... 27 
5.3 BLINDING & OTHER MEASURES TAKEN TO AVOID BIAS ............................................................. 27 
5.3.1 BLINDING ................................................................................................................................. 27 
5.3.3 CODEBREAKING / UNBLINDING ............................................................................................... 28 
5.4 INTEGRATED QUALITATIVE OUTCOME MEASURES .................................................................... 28 
5.4.1 TRIAL PARTICIPANTS ................................................................................................................ 28 
5.4.2 HEALTHCARE PROFESSIONALS ................................................................................................. 29 
5.12 INTEGRATED HEALTH ECONOMIC ANALYSES ........................................................................... 32 
5.14 VISIT SCHEDULE......................................................................................................................... 32 
5.14.1.PATIENTS (Main Study) .......................................................................................................... 32 
6 NON-TREATMENT STUDY INTERVENTIONS ................................................................................... 35 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
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6.3 DEMOGRAPHICS, MEDICAL AND UROLOGICAL HISTORY ........................................................... 36 
6.4 LABORATORY TESTS .................................................................................................................... 36 
6.5 MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING (mpMRI) ............................................. 36 
6.6 PROSTATE BIOPSY ....................................................................................................................... 36 
6.7 VALIDATED PATIENT QUESTIONNAIRES ...................................................................................... 36 
7 FOLLOW-UP .................................................................................................................................... 37 
8 STUDY COMPLIANCE AND PARTICIPANT WITHDRAWAL ................................................................... 40 
9 PHARMACOVIGILANCE/ ADVERSE EVENT REPORTING ...................................................................... 42 
9.1 ADVERSE EVENT (AE) .................................................................................................................. 42 
9.1.4 ABNORMAL LABORATORY TEST RESULTS ................................................................................ 43 
9.2 SERIOUS ADVERSE EVENTS (SAE) ................................................................................................ 43 
9.3 ANNUAL PROGRESS REPORTS ..................................................................................................... 46 
9.4 PREGNANCY ................................................................................................................................ 46 
9.6 REPORTING URGENT SAFETY MEASURES ................................................................................... 46 
10. STATISTICAL ANALYSES ................................................................................................................... 46 
10.1 SAMPLE SIZE AND POWER CONSIDERATIONS .......................................................................... 46 
10.2 PLANNED RECRUITMENT RATE ................................................................................................. 47 
10.3 STATISTICAL ANALYSIS .............................................................................................................. 47 
11. REGULATORY, ETHICAL AND LEGAL ISSUES .................................................................................... 48 
11.1 DECLARATION OF HELSINKI ...................................................................................................... 48 
11.2 GOOD CLINICAL PRACTICE ........................................................................................................ 48 
11.3 CLINICAL TRIALS AUTHORISATION ............................................................................................ 48 
11.4 INDEPENDENT ETHICS COMMITTEE APPROVAL ....................................................................... 48 
11.5 HRA APPROVAL ......................................................................................................................... 49 
11.7 NON-COMPLIANCE AND SERIOUS BREACHES ........................................................................... 49 
11.9 INSURANCE AND INDEMNITY AND SPONSOR........................................................................... 49 
11.10 TRIAL REGISTRATION .............................................................................................................. 50 
11.11 INFORMED CONSENT .............................................................................................................. 50 
11.12 CONTACT WITH GENERAL PRACTITIONER .............................................................................. 52 
11.13 PARTICIPANT CONFIDENTIALTY .............................................................................................. 52 
11.14 DATA PROTECTION.................................................................................................................. 53 
11.15 END OF TRIAL .......................................................................................................................... 53 
12. DATA MANAGEMENT, STUDY DOCUMENTATION AND DATA STORAGE ........................................ 53 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
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12.1 SOURCE DATA ........................................................................................................................... 56 
13.2 LANGUAGE ................................................................................................................................ 56 
13.3 DATABASE ................................................................................................................................. 56 
13.4 DATA COLLECTION .................................................................................................................... 56 
13.5 ARCHIVING ................................................................................................................................ 57 
14. STUDY MANAGEMENT STRUCTURE ................................................................................................ 57 
14.1 TRIAL STEERING COMMITTEE (TSC) .......................................................................................... 57 
14.2 TRIAL MANAGEMENT GROUP (TMG)........................................................................................ 57 
14.3 DATA MONITORING COMMITTEE (DMC) .................................................................................. 58 
14.4 EARLY DISCONTINUATION OF THE STUDY ................................................................................ 58 
14.5 RISK ASSESSMENT ..................................................................................................................... 58 
14.6 MONITORING ............................................................................................................................ 58 
14.7 QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................ 58 
14.8 PEER REVIEW ............................................................................................................................. 58 
14.9 PATIENT AND PUBLIC INVOLVEMENT ....................................................................................... 59 
14.10 PUBLICATION AND DISSEMINATION POLICY .......................................................................... 59 
16. REFERENCES .................................................................................................................................... 60 
SIGNATURE PAGE 1 (Chief Investigator) ........................................................................................... 66 
SIGNATURE PAGE 2 (Sponsor) .............................................................................................................. 67 
SIGNATURE PAGE 3 (Statistician) .......................................................................................................... 68 
SIGNATURE PAGE 4 (Principal Investigator) ......................................................................................... 69 
 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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Page 9 of 71 
 
TRIAL SUMMARY 
TITLE 
PROState Pathway Embedded Comparative Trial  
AIM 
• 
To assess the feasibility and acceptability of a cohort multiple randomised 
controlled trial (cmRCT) in patients with prostate conditions 
• 
To assess acceptance rates to entry into the cohort  
• 
To assess acceptance to future randomised interventions or changes in 
management to compare against standard care 
• 
To assess acceptance to future embedded randomised interventions (changes in 
diagnostic and therapeutic pathways)  
• 
To assess the feasibility of collecting regular health status and clinical data as well 
as patient reported outcomes (PROMS) within the cohort  
DURATION 
PILOT 
• 
Months 0 – 6: Set-up 
• 
Month 7 – 16: Recruitment 
• 
Months 17 – 22: Close out and analysis 
MAIN STUDY 
• 
Months 1-8 cohort recruitment 
• 
Months 9-18: Embedded randomised interventions 
• 
Months 19-24: Longitudinal follow-up 
DESIGN 
Cohort Multiple Randomised Controlled Trial (cmRCT) design 
(aka Trials Within Cohorts [TWICS]) 
SAMPLE SIZE 
Acceptability and Feasibility sample size: 80 patients 
 
The actual cohort sample will not be restricted as the overall number needed will 
be dependent on future randomised interventions and therefore there is no 
maximum number. If the feasibility number is met then we will continue recruiting 
for the entire recruitment period with no upper limit on numbers and continue 
beyond the existing recruitment period if further funding allows and pending 
approval by REC. 
ACCEPTABILITY 
OBJECTIVES 
• 
To determine what proportion of patients with a clinical suspicion for prostate 
cancer will participate in an cmRCT.  
• 
To evaluate the proportion of patients approached agreeing to participate in the 
longitudinal cohort from men approached for take part. 
• 
To explore barriers and facilitators to the implementation of a cmRCT in order to 
improve and inform patient and/or physician trial information, study processes, 
interventions, and recruitment and retention of patients.  This will be carried out 
by qualitative assessments in the following areas. 
- 
 To investigate by interview the patient experiences and perspectives on: 
 
Trial participation, 
 
The point at which men are approached by the research team to 
enter the cohort, 
 
Barriers and facilitators to consent to participate in the cohort, 
 
Barriers and facilitators to consent to future random selection to 
undergo a healthcare intervention or change in management,  
 
Acceptability of monitoring of health status and the tools used to 
do this in the cohort. 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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- 
To investigate by interview the experiences and perspectives of healthcare 
professionals (doctors and clinical nurses, research staff, NHS admin and 
management) on; 
 
Trial design and information given to patients and healthcare 
professionals, 
 
Feasibility of random selection of participants to future 
interventions, 
 
Tools used for measuring health status. 
FEASIBILITY 
OBJECTIVES 
• 
To determine the feasibility of recruitment and logistical implementation of 
different data collection in centres based in different institutions.  This will be 
broken down into the following sub-questions; 
o 
Evaluating how the patients are successfully identified and the option of 
how inclusion in the trial is presented to them. 
o 
Evaluating the practicalities of the consent process and of presenting the 
invitation. 
o 
Evaluate PROMS response rates at baseline and pre-determined intervals 
following from the point of recruitment into the study and explore factors 
that can promote optimal patient response rate and thereby improve data 
collection. 
o 
To evaluate completeness and fidelity of clinical data on the men who 
participate in the cohort. 
ELIGIBILITY CRITERIA 
Inclusion Criteria 
Patients 
1. Men aged 18 years old and over who are referred for investigations for 
urinary symptoms or elevated serum prostate specific antigen (PSA) levels 
or other risk factors for possible prostate malignancy OR Men aged 18 
years or older with a diagnosis of prostate cancer on active surveillance or 
referred from another centre for consideration of surgery, radiotherapy or 
ablative therapy to the prostate. 
2. An understanding of the English language sufficient to understand written 
and verbal information about the trial and consent process. 
3. Estimated life expectancy of 5 years or more. 
4. Signed informed consent. 
Healthcare professionals 
1. Consultant Urologists, Uroradiologists, Oncologists, Nurses and Urology 
specialty trainees, research and management staff. 
 
Exclusion Criteria 
Patients 
1. Men who are unable to give informed consent. 
Healthcare professionals 
1. 
Not involved in the care of prostate cancer patients in either research, 
clinically and managerial bases. 
ACCEPTABILITY 
ENDPOINTS 
• 
Proportion of those approached consenting to inclusion in the PROSPECT 
cohort at the original point of contact by the research team.   This will be 
calculated on an ongoing basis and will be reviewed at the first 6-month 
timepoint. 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
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• 
To investigate by interview the experiences and perspectives of patients who; 
- 
Consented to inclusion in the cohort study, 
- 
Declined to enter into the cohort, 
- 
Consented to inclusion in the cohort initially but who subsequently 
requested to leave the cohort, 
• 
The opinions of healthcare professionals (clinical and management) involved 
in the care of patients recruited into the cohort.  We will interview at least 5 
doctors and clinical nurses, up to 5 research staff and up to 5 management 
staff.  We will conduct interviews at 6 and 12 months from the opening of 
PROSPECT (as appropriate) following thematic analysis of the initial 
interviews. We will perform semi-structured interviews that focus on 
implementation, practicality and efficiency of PROSPECT.   
 
FEASIBILITY 
ENDPOINTS 
• 
Evaluation of the number of men approached to enter PROSPECT against the 
number of men referred to the participating centres for investigation of 
prostate cancer.   
• 
We will conduct a review of the pathway by which we approach men to invite 
them to the cohort.  Part of this will be included in the qualitative interviews 
with men and healthcare professionals.  Particular points of interest will be the 
timing of consent process, the trial personnel who gain consent, and the 
number of men who give consent who are subsequently not diagnosed with 
prostate cancer.  
• 
Participants will be given a standard Quality of Life Questionnaire (EQ5D-5L) at 
the point at which they consent to inclusion into PROSPECT. We will calculate 
the completeness of this data one year after opening and on an ongoing basis. 
• 
All participants will be asked to complete PROMS on disease specific quality of 
life at the following points; 
o 
Recruitment to cohort. 
o 
0-6, 6, 12, 18 & 24  months from recruitment to cohort 
o 
Yearly questionnaires thereafter during inclusion in the cohort and 
provided the study is open.  
o 
Once the primary outcome measures are reached (approx. 80 
patients), the follow up period will be reduced to 3 months. 
• 
Feasibility of collecting data from the participating centres evidenced by 
the completeness of data for cohort participants including: 
o 
Subject Data: age, co-morbidities, ECOG/WHO Performance 
Status, ethnic risk, family history 
o 
Disease Characteristics: PSA, MRI (prostate volume, MRI score), 
biopsy type and findings, TNM stage if cancer 
o 
Treatment 
Data: 
modality, 
follow-up, 
adjuvant/salvage 
treatments, mortality 
o 
We will conduct this analysis at one year after opening PROSPECT 
and yearly thereafter, as long as the study is open, in order to 
monitor any trends in data return on participants.  
o 
Once the primary outcome measures are reached (approx. 80 
patients), the follow up period will be reduced to 3 months. 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
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1. BACKGROUND 
1.1 SUMMARY 
Traditionally, level one evidence is obtained from two-arm, or 3-arm, randomised controlled 
trials (RCT) of a new treatment(s) and compare it to an established treatment in which neither 
the patient nor the doctor knows who is taking what, until the end of the study (‘double-
blind’). The treatment allocation is based on chance and the blinding minimises bias. When 
one of the treatments is surgery this design may not always be ethical or practical. 
Unfortunately, in trials involving surgery or complex interventions, a variety of factors can 
lead to the failure to accrue sufficient participants in many traditional RCT designs. This has 
been particularly highlighted in localized prostate cancer RCTs, where 12 RCTs evaluating 
different interventions in localised prostate have failed to recruit, many in the last 5 years. 
The same issue has occurred recently in trials of localized bladder cancer (surgery versus 
radiotherapy) and renal cancer (surgery versus surveillance; surgery versus ablation) as well 
as other non-urological disease spaces. 
Our proposal will explore a trial design called the cohort-multiple RCT (cmRCT) or as it has 
been recently coined, the Trials WithIn Cohorts (TWICS) design. This design has been used in 
a number of disease areas, both benign and cancer. We have chosen prostate conditions since 
they are extremely common and if malignancy occurs the majority of men with the disease 
are regarded as living with a chronic condition due to its long natural history and in which 
innovative approaches, interventions, treatments or changes in management might have a 
significant patient benefit and impact on the NHS. It therefore fits the cmRCT design very well. 
Nonetheless, the lessons we learn in this study will be of relevance to other disease spaces. 
The TWICS or cmRCT design is currently being used in elderly patients, risk of falls, depression, 
hip fracture, Yorkshire Health Study, scleroderma, breast cancer, colorectal cancer, bladder 
cancer and kidney cancer, to name a few. In total, a recent systematic review showed that 
there were 18 ongoing cmRCT studies with 6 in the UK.  
We want to test the acceptability and feasibility of the cmRCT in the prostate pathway. As this 
is the first time that we are trying out this method we need to first pilot it. In the first part of 
the study, we want to evaluate the following. What is the accrual rate? What do patients and 
their healthcare professionals think of the cmRCT design? Is the data we collect robust? What 
are the resource requirements of such a study? We will then test a number of novel 
interventions or changes in the pathway and compared them to standard care in the cohort 
that we recruit. 
 
1.2 RATIONALE FOR PROSPECT 
Recently published RCTs have reinforced the limitations and uncertainty of current diagnostic 
and therapeutic pathways for men with prostate cancer(1). Two RCTs (PLCO (2) and EPSRC 
(3)) compared screening (10yr lead-time bias) to no screening and demonstrated no overall 
survival benefit and a small prostate-cancer specific survival benefit in EPSRC. However, there 
was significant over-diagnosis and over-treatment (4). Another two RCTs compared surgery 
versus watchful waiting. SPCG4 showed improved all-cause and prostate-specific mortality in 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
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Page 13 of 71 
 
unscreened men with absolute reductions of 6% at 15 years(5). PIVOT showed no 
improvement in overall or prostate cancer-specific mortality in men detected in the early PSA-
screening era (absolute mortality differences <3%) (6,7). Equally, preliminary results from a 
trial of external beam radiotherapy showed no benefit in overall or disease-specific mortality 
compared to watchful waiting among men with non-PSA detected clinically localized prostate 
cancer (8). The recent PROTECT RCT showed no cancer specific survival differences between 
the three arms of radical prostatectomy, radical radiotherapy and active monitoring in men 
diagnosed as a result of PSA screening; PROTECT did show improvements in metastases-free 
survival using radical therapy overactive monitoring [9]. All these studies demonstrate that 
there is significant uncertainty around treatment options for men with prostate cancer and 
therefore a need for further comparative effectiveness research to guide treatment options. 
The problem is that doing trials in which the interventions are significantly different and in 
which one arm contains surgery has always been difficult. We recently conducted a review of 
all RCTs in prostate cancer treatment evaluations that have failed to accrue over the last 10 
years (10). We found five UK and six international RCTs evaluating novel interventions in non-
metastatic prostate cancer that closed prematurely due to slow recruitment usually resulting 
from lack of patient and physician equipoise. This was despite pre-RCT feasibility 
questionnaires and surveys demonstrating that there was apparent equipoise on the research 
question to warrant these RCTs.  
There have been certain exemplar cases that have succeeded such as the ProtecT study (11) 
and PIVOT (12). However, the cost to achieve this has been high (PROTECT £25M; PIVOT $8M). 
Moreover, they have been slow to initiate (2-4yrs) and report (10-15yrs) leading to physicians 
questioning their external validity when they do eventually report [13-15]. A recent RCT 
funded by the NIHR-HTA in the UK, called PART, struggled to accrue (16) with another, SPCG-
15, run by the very successful Scandinavian Prostate Cancer Group has also failed to accrue 
(17). The SPCG successfully conducted SPCG4 – the RCT of watchful waiting versus surgery 
from about 20 years ago - so this points to the current climate for running comparative 
effectiveness research having changed since SPCG4, PIVOT and ProTecT. Recently, other 
urological RCTs comparing different treatments in bladder cancer and renal cancer have also 
failed to accrue [18-20]. The problems with RCTs in surgery, particularly, have been 
comprehensively reviewed recently in an UK National Cancer Research Institute review (21). 
Persisting with our current model of acquiring evidence in this space therefore has a high 
chance of failing. The alternative, because we struggle to recruit to standard RCTs, is to give 
up and stop further innovations being evaluated within robust RCTs. Neither option is 
appropriate or acceptable. The third option is to determine whether a novel trial design might 
work (22). The European Medicines Agency states in one of its guidelines that “One approach 
for a given study might be to consider the study population as a cohort in which to implement 
the most appropriate design for each objective, thus ensuring alignment of each objective to 
the best possible design and analysis” (23). Further, the MRC Guidelines for Evaluating 
Complex Interventions states that novel designs could be justified in areas of difficulty in 
conducting standard RCTs (24). Namely, “Preference trials and randomised consent designs: 
Practical or ethical obstacles to randomisation can sometimes be overcome by the use of non-
standard designs. Where patients have very strong preferences among treatments, basing 
treatment allocation on patients’ preferences, or randomising patients before seeking 

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consent, may be appropriate.”  Certainly, in the area of prostate diseases, high quality clinical 
research and investigation of novel strategies in patients with prostate diseases has been 
sufficiently difficult in the recent past, so that the evaluation of a new way of running clinical 
trials is warranted. 
 
The Cohort Multiple RCT  
We propose using the cohort-multiple RCT (cmRCT) or the Relton/Nicholls design (25) also 
known as the Trials WithIn Cohorts (TWiCS). Others have recently supported the evaluation 
of such designs and many RCTs are now successfully underway using it (26).  
A more detailed account of the study design will be covered in the next section (Section 3).  
This approach is currently being evaluated in ethics committee approved studies in a variety 
of diseases, such as depression (NIHR-HTA CASPER, 08/19/04) (27, 28); NIHR DiRECT (Exeter) 
(29)), obesity (30, 31), falls in the elderly (NIHR-HTA REFORM, 09/77/01) (32), cognitive 
behavioural therapy in schizophrenia (Canadian Institute of Health Research (33)), prevention 
of cardiovascular disease through a polypill (34, 35), ulcerative colitis (NIHR-HTA CONSTRUCT, 
06/78/03) (36), elderly care (NIHR HS&DR 12/130, CLASSIC (Salford) and scleroderma (37).  
The £1.5M funded bladder cancer ‘Roberts Study’ and the MRC (UK) funded NEST Study in 
kidney cancer are both cmRCTs in Kings College London (REC: London - Fulham Research 
Ethics Committee 17/LO/1975 [38] and The Royal Free Hospital (East Midlands - Derby 
Research Ethics Committee 19/EM/0004, respectively [39]. 
In the Netherlands the cmRCT design has also been approved for the investigation of new 
cancer interventions.  The University of Utrecht is successfully running cmRCTs in colorectal 
cancer (alongside the Dutch Colorectal Cancer Group), breast cancer and cancers with spinal 
metastases (PICNIC) (40-46). The Utrecht group have successfully recruited to all three 
cohorts with 80-90% of those patients approached so far accepting both consent to the cohort 
and consent to future random selection for new (but un-named) treatments. So far, between 
October 2013 and July 2016, they have recruited 1,308 participants. In this period, 1308/1486 
(88%) patients who were invited for participation in UMBRELLA consented to cohort 
participation. Of these patients, 1138 (87%) gave broad consent for randomisation to future 
interventions. Return rate for PROMs at baseline was 80% and varied from 67 to 74% during 
follow-up [40,47].  
 
 
 
 
 
 

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Figure 1b: UMBRELLA study of breast cancer cohort showing staged consent (from Young-
Afat et al, 2016) 
 
 
Figure 1b: UMBRELLA study of breast cancer cohort showing staged consent (from Gal et al, 
2019) 
 
 

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The cmRCT design and longitudinal framework seems to be successful in conditions where 
patients affected may transition from different health states over time.  The cmRCT design 
also works well in spaces where Patient Reported Outcome Measures (PROMs), healthcare 
utilisation and vital status are important outcome measures.  Research of patient outcomes 
in non-metastatic prostate cancer and benign prostate disease is similar to the outcomes of 
interest in chronic diseases in many respects and as such we believe the cmRCT will lend itself 
well to the investigation of novel interventions in prostate conditions. If successful, the design 
could be evaluated in other disease processes in which RCTs are traditionally difficult to 
deliver to.  
Our proposal for a cmRCT approach has several other potential advantages in that it might 
allow greater access to RCTs than the current trial system since all eligible men have an equal 
chance of being recruited. It might also avoid disrupting existing service provision as well as 
being able to run trials in a very efficient and cost-saving manner (48). The cmRCT design that 
we propose represents a potential paradigm shift in the way we might conduct comparative 
effectiveness research and will allow us to investigate new interventions using a robust 
method in difficult-to-recruit disease spaces.  
Our proposal seeks to reverse the order in which the question and the framework are realised. 
Typically, “infrastructure” follows a “question” and the infrastructure is disbanded after the 
trial. We propose to first establish the infrastructure (cohort) in a defined geographic 
population with case ascertainment, PROMs for functional and vital status, linkage to local 
institution records for prostate disease status, linkage to national databases for healthcare 
utilisation and linkage to death registries. Key questions could in future be addressed by 
embedding multiple RCTs into this infrastructure such as refining surgical techniques; 
methods to manage side-effects of different treatments; monitoring strategies after different 
therapies; surgical methods; and pre-operative targeted molecular therapies. 
A Lancet editorial discussed the virtues of trial designs that consider multiple interventions, 
at the same time showing that trial costs could be halved by doing so (49). So for instance, if 
we were just to run 3 separate RCTs then each trial would cost an estimated £7.8 million. Our 
proposed trial design, if successful, would allow additional research questions to be answered 
at less cost to funders and in a more timely fashion to benefit patients and the NHS. A further 
attraction of the cmRCT that warrants explicit consideration here is the beneficial 
consequences on power calculations and rate of recruitment to prospective trials from 
already having the control group in place.  This will allow quicker completion of trial accrual, 
faster publication of results, increased trial efficiency and reduced trial waste and 
redundancy.  These are important, as there has been a lot of debate recently about the delays 
that are incurred through trial set-up (50, 51). 
Patient and public involvement is at the core of all our research from conception to delivery. 
The Chief Investigator has presented the issues around this to 40 members of the Mount 
Vernon Prostate Support Group and with the Maggie’s Cancer Centre Prostate Support Group 
in Charing Cross Hospital. All the men present stated a reluctance to participate in head-to-
head RCTs, but discussions around the novel cmRCT design were positive. A number of men 
in this focus group commented that the cmRCT would lead to greater patient access to trials 
and innovative therapies. The results of these deliberations were published (52). 

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Our group also conducted a consensus meeting of 63 members, facilitated by the Chief 
Investigator, to consider trial designs for localized prostate cancer. There were five patient 
representatives alongside triallists and methodologists as well as physicians [10]. The patient 
and public representatives provided key input into all discussions at whole group level and 
within break-out sessions. They again stated a reluctance to participate in head-to-head RCTs, 
whilst accepting the need for robust data to change practice. The group reinforced the need 
to consider alternative trial designs that might be more acceptable to patients and support 
recruitment [10]. This proposal has thus originated from patient concerns and has a design 
largely driven by involved patients and public as well as key trial methodologists and experts 
in the field. 
 
1.3 TRIAL AIMS 
In the pilot phase of PROSPECT we are interested in investigating the a) acceptability and 
feasibility of establishing the cohort of men, i.e. putting the questions of Point of Consent One 
to men being referred for investigation of prostate cancer, and b) observing the cohort over 
the study period and collecting data on the participants pertaining to their disease, their 
treatment and their health status.  
 
A) Acceptability 
AIM 1.1: To determine what proportion of men with a clinical suspicion for prostate cancer 
will participate in a cmRCT.  
OBJECTIVE 1.1a: To evaluate proportion of patients approached who agree to participate in 
the longitudinal cohort.  This will be done by calculating the participation rates from men 
approached for invitation to PROSPECT. 
AIM 1.2: To explore barriers and facilitators to implementation of a cmRCT in order to 
improve and inform patient and/or physician trial information, study processes, 
interventions, and recruitment and retention of patients.  This will be carried out by 
qualitative assessments in the following areas. 
OBJECTIVE 1.2a:  To investigate by interview the patient experiences and perspectives on;    
- Trial participation, 
- The point at which men are approached by the research team to enter the cohort, 
- Barriers and facilitators to consent to participate in the cohort, 
- Barriers and facilitators to consent to future random selection to undergo a new 
healthcare intervention,  
- Acceptability of monitoring of health status and the tools used to do this in the 
cohort. 

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OBJECTIVE 1.2b: To investigate by interview the experiences and perspectives of healthcare 
professionals (doctors, nurses and admin staff) on; 
- Trial design and information to patients and healthcare professionals, 
- Feasibility of future random invitation of participants to interventions, 
- Tools used for measuring health status. 
 
B)  FEASIBILITY 
AIM 2.1:  To determine the feasibility of recruitment and logistical implementation of 
PROSPECT in different data collecting centres based in different institutions.  This will be 
broken down into the following sub-questions; 
OBJECTIVE 2.1a:  Evaluating how the patients are successfully identified and the option of 
how inclusion in the trial is presented to them. 
OBJECTIVE 2.1b: Evaluate patient questionnaire response rates for pre-treatment quality of 
life. 
OBJECTIVE 2.1c: Evaluate patient questionnaire response rates at pre-determined intervals 
following on from the point of recruitment into the trial to determine how we might promote 
optimal patient response rate and improve data collection. 
OBJECTIVE 2.1d: To evaluate completeness and fidelity of clinical data on the men who 
participate in the cohort.  
 
2. OUTCOMES AND ENDPOINTS  
2.1. ACCEPTABILITY OUTCOMES 
OUTCOME 1.1a.   Rate of consent to inclusion to PROSPECT cohort at the original point 
of contact by the research team.   This will be calculated on an ongoing basis and will be 
reviewed at 6 months and one year from opening and at the end of the study period  
OUTCOME 1.1b. To investigate by interview the experiences and perspectives of patients 
who: 
- Consented to inclusion in the cohort study, 
- Declined to enter into the cohort, 
- Consented to inclusion in the cohort initially but who subsequently requested to 
leave the cohort, 
We will perform structured thematic interviews. Initially, we will aim to interview at least five 
men who consent to participate in PROSPECT and at least 5 men who decline to participate 
in PROSPECT.  We will also ask to interview any men who initially agree to participate in 

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PROSPECT who subsequently ask to be withdrawn. We will use purposive sampling to ensure 
our sample relates to the UK population in terms of wealth / income, ethnicity and age.  Men 
will continue to be approached for interview until the qualitative sample is representative of 
these factors. Recruitment for qualitative interviews will continue until no further themes 
emerge. 
Interviews will be conducted by the researchers who will follow the Interview Questionnaire 
Template whilst allowing for some flexibility in the direction and emphasis of the discussion. 
The templates are formed of a group of pre-determined topics and open questions to explore 
them. More direct closed questions may be used subsequently with flexibility as above.  The 
interviews will be recorded and transcribed in house before analysis and theme-based 
extraction of the reasons behind men’s decision regarding inclusion in the cohort.  Direct 
quotes may be used in subsequent publications, but these will always be non-identifiable to 
the individual interviewed.  If during the course of the five interviews feedback demonstrates 
new emerging themes, then consideration will be given to interviewing more men in order to 
give a broad and fully representative picture of the reasons behind men’s decisions. Results 
from the thematic interrogation of these interviews will be formally fed back to the TMG as 
well as put into writing for peer-reviewed publication. 
OUTCOME 1.1e.  The opinions of healthcare professionals who regularly look after men 
with prostate problems will be sought.  We will interview at least 5 doctors and nurses and 
if necessary up to 10, up to 5 research and management staff.  We will conduct interviews 
at 6 and 12 months from the opening of PROSPECT, as appropriate depending on the first 
round of responses. We will perform semi-structured interviews that focus on 
implementation, practicality and efficiency of PROSPECT.  There will be a different Interview 
Questionnaire Template for interviews with healthcare professionals.   
 
2.2. FEASIBILITY OUTCOMES 
OUTCOME 2.1a:  Evaluation of the number of men approached to enter PROSPECT against 
the number of men referred to the participating centres for investigation of prostate cancer.   
OUTCOME 2.1b:  We will conduct a review of the pathway by which we approach men to 
invite them to the cohort.  Part of this will be included in the qualitative interviews with men 
and healthcare professionals.  Particular points of interest will be the timing of consent 
process, the trial personnel who gain consent, and the number of men who give consent who 
are subsequently not diagnosed with prostate cancer.  
OUTCOME 2.1c:  Participants will be given a standard Quality of Life Questionnaire (EQ5D-5L) 
at the point at which they consent to inclusion into PROSPECT. We will calculate the 
completeness of this data at 6 and 12 months after opening and on an ongoing basis as long 
as the study is open. 
NB - Once the primary outcome measures are reached (approx. 80 patients), the follow up 
period will be reduced to 3 months. 

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OUTCOME 2.1d:  All participants will be asked to complete questionnaires on disease specific 
quality of life at the following points; 
 
-  Recruitment to cohort. 
-  0-6, 6, 12, 18, 24 months from recruitment to cohort 
-  Yearly questionnaires thereafter during inclusion in the cohort if trial remains open 
(i.e., post pilot phase).  
NB - Once the primary outcome measures are reached (approx. 80 patients), the follow up 
period will be reduced to 3 months. 
 
We will use three self-reporting quality of life validated questionnaires. The responses from 
the questionnaires will be of value as they will provide an informative vignette of the 
experience of men after the diagnosis of prostate cancer and we can compare these against 
the experience of men who are investigated for but not diagnosed with prostate cancer.  In 
terms of evaluating the feasibility of the cmRCT design, PROSPECT will calculate the rates of 
response from participants with these questionnaires.  Questionnaire response rates will also 
inform our understanding of the acceptability of the cmRCT design study to patients. 
 
OUTCOME 2.1e:  Feasibility of collecting data from the participating centres evidenced 
by the completeness of data for cohort participants including; 
i.   Subject Data: age, co-morbidities, ECOG/WHO Performance Status, ethnic risk, family 
risk 
ii.  Disease Characteristics: PSA, MRI (volume, score), biopsy findings (cancer or not, grade 
if cancer, length of maximum cancer, other pathology), TNM stage if cancer 
iii.  Treatment Data: modality, follow-up, adjuvant and salvage treatments, mortality 
We will conduct this analysis at one year after opening the PROSPECT and yearly thereafter 
in order to monitor any trends in improving or faltering data accrual on participants, as long 
as the study is open.  
 
3. STUDY DESIGN  
3.1 Design 
The key features of a cmRCT are; 
1. Explicitly consented recruitment of a large cohort of patients with the condition of 
interest. 
2. Regular measurement of relevant outcome measures for the whole cohort 
prospectively in the long-term. 

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3. Facility to re-approach cohort participants, who are randomly selected from eligible 
patients within the cohort, inviting them to undergo intervention of interest to 
researchers with eligible patients not randomly selected entering the control standard 
care group (see study flowchart 3.3 / 3.4). 
4. “Patient-centred” informed consent.  The consent process aims to replicate that used 
in the routine health care setting.  Once the patient has been randomly selected for a 
randomised novel intervention from the eligible patients within the cohort, the 
second consent process should include detailed and specific information pertaining to 
the particular intervention or change in management they are being invited to 
undergo for comparison. Such information will be written and advised using patient 
representatives and undergo review following submission to REC. 
5. Comparison of the outcomes in the randomly selected patients with the outcomes in 
eligible patients not randomly selected.  
6. Capacity for multiple randomised controlled trials over time within the cohort 
simultaneously. 
This structure can be seen in the cmRCT flow diagrams (Section 3.3, 3.4). 
 
3.2 CONSENT 
For men who are participating in the cmRCT there are two points of consent: 
 
3.2.1 POINT OF CONSENT ONE 
At Point of Consent One men who are referred for investigation of prostate cancer will be 
asked two questions.  The first question relates to whether they are willing to join the cohort 
and have data collected directly from them over time on a regular basis. This data will include 
health-related quality-of-life data (at recruitment, 0-6, 6, 12, 18 & 24 months post 
recruitment), linkage to their medical records so that researchers can know what happens to 
them over time, and access to other data about them held on national health registry 
databases. Also, at point of consent one, prospective participants will be asked (second 
question) whether they agree to being randomly selected in the future to interventions or 
changes in management in order to compare to standard care. We will explain that this 
second invitation will be on a random basis. In other words, everyone eligible within the 
cohort will have the same chance of being randomly selected. The patient would still have the 
option of saying ‘no’ after the random selection when they are approached. 
 
3.2.2 POINT OF CONSENT TWO 
The second point of consent is the invitation to undergo an intervention or change in 
management that the research team wishes to compare to standard care.  Participants will 

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have already agreed to the possibility of being invited to undergo intervention at Point of 
Consent One (i.e. enrolment into the cmRCT).  The participant will have been randomly 
selected from amongst all the eligible men for the given intervention from within the large 
cmRCT cohort prior to being approached by the trial team.  Then, the trial team will approach 
the participant and invite him to undergo the intervention.  This will entail a comprehensive 
consent process that pertains directly to the intervention being proposed in a patient-centred 
manner.  The participant can agree or refuse to undergo the intervention.   If he does not wish 
to undergo the treatment he will continue under follow-up in PROSPECT.   
Participants undergoing intervention will continue to have follow-up in the same manner as 
men who have not been randomised from within the cohort and thus provide outcome data 
to form the control arm.  Comparison of the outcomes of those men who underwent trial 
intervention against those who did not will allow us to analyse the effectiveness of the 
intervention in as robust a manner as possible given that the key feature of randomisation 
when creating the control vs. the intervention arms has been preserved.  As such, the control 
arm of the cmRCT will be similar to the intervention arm in all features, known and unknown, 
except the intervention of interest. This will allow us to maintain the epistemological 
superiority of the data we produce for evaluating new tests or treatments whilst getting to 
this point in a way that might be more acceptable to patients and therefore more likely to be 
successful and efficient for researchers. 
The second stage of PROSPECT will be to investigate and evaluate in a similarly careful manner 
the feasibility and acceptability of randomising men from our cohort of eligible men to 
interventions or changes in management that require evaluation, following submission to 
REC.  As part of the cmRCT design, these men randomly selected are re-approached and 
invited to consider undergoing the intervention of interest. Patients who are randomly 
allocated to the control arm will also receive standard of care, and are not informed about 
their participation in the control arm. This additional consent will be obtained at the time of 
consent for the cohort study. 
 
 
 
 
 
 
 
 
 
 

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3.3. PROSPECT cmRCT OVERALL FLOWCHART   

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3.4. AREAS TO BE INVESTIGATED BY PROSPECT 

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4. PARTICIPANT ENTRY 
4.1 STUDY SETTING AND POPULATION 
We wish to include all men referred for investigation of prostate cancer. The inclusion criteria 
for our cohort are deliberately broad.   

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4.2 INCLUSION CRITERIA 
1. Men aged 18 years old and over who are referred for investigations for urinary 
symptoms or elevated serum prostate specific antigen (PSA) levels or other risk 
factors for possible prostate malignancy OR Men aged 18 years or older with a 
diagnosis of prostate cancer on active surveillance or referred from another centre 
for consideration of surgery, radiotherapy or ablative therapy to the prostate 
2. An understanding of the English language sufficient to understand written and verbal 
information about the trial and consent process. 
3. Estimated life expectancy of 5 years or more. 
4. Signed informed consent. 
 
4.3 EXCLUSION CRITERIA 
1. Men who are unable to give informed consent. 
 
5. PROCEDURES AND MEASUREMENTS  
5.1 IDENTIFICATION AND RECRUITMENT OF PATIENTS 
No participant will be paid to participate in the study. All men who meet the eligibility criteria 
for inclusion in the cohort will be contacted by the dedicated Research Team Recruitment 
Officer (e.g., Research Nurse / Clinical Trial Practitioner, Research/Clinical Fellow) in each 
participating centre.   
Potential participants will be men who are referred to the respective centre for investigation 
of their prostate for possible malignancy as part of the NHS suspected cancer referral system. 
The NHS clinical team will make contact with each man as normal, to organise their first 
appointment and inform them that the study recruitment may approach them to discuss the 
trial.   
The dedicated Research Team Recruitment Officer will contact the eligible men remotely 
before the patient is seen in clinic. The patient will be asked for permission to send him the 
literature pertaining to the PROSPECT study including REC approved PIS, ICF and contact 
information for the research team along with the patient invitation letter.  All men will have 
the opportunity to discuss all aspects of the study with their GP, family members, and their 
Recruitment Officer prior to the clinic appointment at their participating centre.  
On the day of appointment at the participating centre patients will be seen by a member of 
the research team (Clinical Research Fellow, Clinical Research Nurse, Clinical Trial 
Practitioner) either in person or remotely, where they meet the clinical team who will lead 
the usual care investigation for their prostate.  At this point, the PROSPECT study will be 

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described to them again and the patient will be asked whether they would like to participate.  
If they agree to participating, they will be given the option to consent to the study remotely 
using e-consent or through the more traditional paper-based approach. 
The patient will be asked to sign the REC approved ICF. The fully signed original copy will be 
kept in the Investigator’s Site File, a copy will be provided to the patient and a further copy 
will be placed in the patients’ medical notes and the consent process documented. Consent 
will be obtained by one of the research team who has been trained to GCP standards and 
delegated to this task.  The patient will also be given the quality of life questionnaires to 
complete. This can be in one of three ways. First, via a link to the questionnaire via the 
participant’s email address that input directly into the eCRF. Second, the questionnaire is 
filled out on a university tablet device which inputs directly into the eCRF. Third, on paper if 
neither of the first options is possible. Paper questionnaires can either be completed in clinic 
and given straight to the research team or taken home and returned by post.     
 
5.2 SCREENING EVALUATIONS 
Potential participants will be men who are referred to the respective centre for investigation 
of their prostate for possible malignancy.  The dedicated Recruitment Officer will contact the 
eligible men remotely before the patient is seen in clinic.  The patient will be asked for 
permission to send him the literature pertaining to the PROSPECT study including REC 
approved PIS, ICF and contact information for the research team.  All men will have the 
opportunity to discuss all aspects of the study with their GP, family members, and their 
Recruitment Officer prior to the clinic appointment at their participating centre.  
 
5.3 BLINDING & OTHER MEASURES TAKEN TO AVOID BIAS 
5.3.1 BLINDING 
In the pilot stage of PROSPECT no interventions are being tested. Nonetheless, there are a 
number of measures that will minimise the interference of bias in the collection of our data.  
The following are features that are inherent in the structure of a cmRCT and will also be 
evident in PROSPECT. 
- 
PROSPECT participants are included prior to receipt of treatment, whether this is usual 
standard of care or intervention.  This has two beneficial corollaries for the quality of 
patient data we receive.  Initial questionnaires and quality of life data will represent a 
baseline, and this can also be compared to participants who have no prostate cancer 
moving forward. Furthermore, baseline data will be collected about PROSPECT 
participants and their prostate disease before investigators know whether they will be 
randomised to intervention or whether they remain in the standard of care control.  This 
is in effect a form of blinding as in other trial formats, the randomisation status of the 
patient may already be known to researchers as this important pre-intervention disease 
and subject data is being collected. 

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- 
The inclusion criteria for our cohort are deliberately very broad.  We will include all 
patients referred for investigation of prostate cancer.  The decision to invite a patient to 
the cohort will not rest with the clinicians who treat the men with disease.  Consequently, 
PROSPECT allows for highly equitable access to inclusion in clinical trials.  This will also 
maximise the external validity of the PROSPECT cohort thereby minimising subject 
sampling bias. Our patient group feedback was particularly positive about this aspect. 
 
5.3.2 OTHER MEASURES TO AVOID BIAS 
The following methodological techniques, which are not unique to the cmRCT study design, 
will also be employed to ensure minimisation of bias in PROSPECT. 
- 
Standardisation of patient quality of life assessment using validated questionnaires at pre-
determined timepoints, from recruitment to the cohort/point of referral and eventually 
post-treatment or longitudinal surveillance.  Use of participant self-completed 
questionnaires will avoid interviewer bias in the follow-up assessment. 
- 
Collation of patient quality of life questionnaires will be performed by researchers who 
are blinded to the intervention the man has undergone as all participants will be assigned 
a confidential personal number that does not reveal whether the participant has been 
randomly selected to undergo intervention or control. 
- 
All staff involved in the collection of objective outcomes and/or other data on the men 
included in the cohort will receive training to ensure the standardisation and consistency 
of the measurement and collation of patient data. 
 
5.3.3 CODEBREAKING / UNBLINDING 
Not applicable.  
 
5.4 INTEGRATED QUALITATIVE OUTCOME MEASURES 
5.4.1 TRIAL PARTICIPANTS 
The integrated qualitative component of the PROSPECT trial will explore patients who;  
- Consented to inclusion in the cohort study, 
- Declined to enter into the cohort, 
- Consented to inclusion in the cohort initially but who subsequently requested to 
leave the cohort, 
We will perform structured thematic interviews. Initially, we will aim to interview at least five 
men who consent to participate in PROSPECT and at least 5 men who decline to participate 
in PROSPECT.  We will also ask to interview any men who initially agree to participate in 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
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PROSPECT who subsequently ask to be withdrawn. Recruitment for qualitative interviews will 
continue until no further themes emerge. 
Interviews will be conducted by the researchers who will follow the Interview Questionnaire 
Template whilst allowing for some flexibility in the direction and emphasis of the discussion.  
The interviews will be recorded and transcribed in house before analysis and theme-based 
extraction of the reasons behind men’s decision regarding inclusion in the cohort.  Direct 
quotes may be used in subsequent publications, but these will always be non-identifiable to 
the individual interviewed.  If during the course of the five interviews feedback demonstrates 
new emerging themes, then consideration will be given to interviewing more men in order to 
give a broad and fully representative picture of the reasons behind men’s decisions. Results 
from the thematic interrogation of these interviews will be formally fed back to the TMG as 
well as put into writing for peer-reviewed publication. 
 
5.4.2 HEALTHCARE PROFESSIONALS 
The opinions of healthcare professionals who regularly look after men with prostate cancer 
will be sought.  We will interview at least 5 doctors and nurses and up to 10 if necessary and 
up to 5 research and managerial staff.  We will conduct interviews at 6 and 12 months from 
the opening of PROSPECT.  We will perform semi-structured interviews that focus on ethics, 
implementation, practicality and efficiency of PROSPECT.  There will be a different Interview 
Questionnaire Template for interviews with healthcare professionals.   
 
5.5 STUDY DURATION 
The currently funded study allows for 10 months of recruitment to PROSPECT.  We 
estimate that each participating centre receives 15-20 new referrals for assessment of 
possible prostate cancer each month.  Therefore, we estimate that 180-250 men will be 
approached to consider entering PROSPECT a year. If the pilot phase of the study is 
successful and further funding is awarded to extend PROSPECT, then we will submit a 
substantial amendment for a 6 month transition phase, to extend the recruitment and 
follow-up of the study to 10 years longitudinal follow-up. 
 
5.6 ANALYSIS AND STATISTICAL CONSIDERATIONS 
We wish to assess the acceptability and feasibility of this trial design in men undergoing 
evaluating and subsequently potentially being treated for prostate cancer and other benign 
disease of the prostate.  We will be testing the acceptability of the trial format to patients as 
well as the levels of data return and the quality of data return.  As such, for these endpoints 
we have no formal power calculations for the qualitative aspects. As part of the feasibility 
objectives for this pilot phase, we will measure the numbers of men approached and numbers 
saying yes to point of consent one. Analysis of the consent and participation rates will be 

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around a precision estimate of 30% acceptance to initial consent to the cohort and future 
randomised interventions or change in management. 
 
Acceptability of initial consent sample size 
75 patients are needed to show that 30% of the eligible patients will accept initial consent 
with a 95% CI of ±10%. If we consider a loss to follow up of 5%, then 80 patients will be 
approached. In the less optimistic rate of 10 eligible patients per month, it would take about 
8 months to prove acceptability. 
The actual cohort sample will not be restricted as the overall number needed will be 
dependent on future randomised interventions and therefore there is no maximum number. 
if the feasibility number is met then we will continue recruitment for the entire recruitment 
period with no upper limit on numbers and continue beyond existing recruitment period if 
further funding allows and pending formal application and approval by REC. 
 
Qualitative Sub Study 
An inductive, thematic content analysis will be used. Common themes will be identified on a 
constant basis, organically throughout the whole data set. This analysis is highly dependent 
on the quality of transcription. Thus, all interviews will be recorded and transcribed in the 
manner set out in section 12.5/6 
 
5.7 CONFIDENTIALITY AND DATA STORAGE 
Information regarding study participants will be kept confidential and managed in accordance 
with the GDPR, NHS Caldecott Guardian, the UK policy framework for Health and Social Care, 
and Research Ethics Approval.  
Responsibility for data collection will be taken by a nominated individual at each centre, likely 
to be the Clinical Nurse Specialist/Recruitment Officer.  
Individual patient data from the original visit at the point of recruitment will be collected.  
Data will be collected on electronic Case Record Forms (eCRFs), including baseline, follow-up 
and safety data.  Each participant will be given a unique subject number and subject identifier 
which will be used on all of their study records i.e., pseudonymised. The eCRFs will be held on 
Imperial College London’s secure RedCap server.  
This data will be sent to Imperial College London via one of two routes: (1) a secure online 
database portal (RedCap), (2) on paper through the post in the exceptional case of PROMs 
questionnaires. Once the questionnaires are uploaded to the site’s NHS patient 
administration service data base, AND subject to monitoring these paper documents will be 
destroyed. Note that the PROSPECT study group can only accept responsibility for the data 
after it has arrived in their custody.  

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Structured interviews are to be conducted as part of the qualitative sub study. These will 
either be conducted remotely or in the field i.e. at a site. In the case of the former, the 
interview will be recorded on a University dictaphone and stored in secure University 
cabinets. In the case of the latter the interview will be recorded on a University laptop with 
encrypted hard drive. The recordings will be deleted as soon as it is transcribed in-house and 
checked for accuracy. The transcription is held in secure University Cabinet until 10 years after 
close of study. 
Imperial College London and each participating site (NHS Trust) recognise that there is an 
obligation to archive study-related documents at the end of the study (as such end is defined 
within this protocol). The Chief Investigator confirms that he/she will archive the study master 
file at ICTU-Surgery for the period stipulated in the protocol and in line with all relevant legal 
and statutory requirements. The Principal Investigator at each participating site agrees to 
archive his/her respective site’s study documents for 10 years and in line with all relevant 
legal and statutory requirements. 
The data will be retained by Imperial College London until 10 years after the final publication 
from the trial according to Imperial College London guidelines.  Specific details regarding data 
storage and destruction are covered in a separate document available from ICTU on request. 
 
5.8 PARTICIPANT IDENTIFIABLE INFORMATION 
Only authorised individuals will have access to person identifiable data. The Trial 
Management Group makes a commitment to maintaining the confidentiality, safety, security 
and integrity of all confidential and sensitive data, which is held under its guardianship. Staff 
in pilot study are obliged to fully comply with The Data Protection Act 2018, together with all 
relevant rules of the sponsor organisation (Imperial College, London). 
All electronic personal identifiable data will be kept separate from pseudonymised data. The 
study database is held on a dedicated Imperial College London database server. Access to 
server and the network is password & access right controlled.  Access to identifiable data is 
controlled by staff roles and passwords.  Patient data will be allowed linkage to national 
registries.  
 
5.9 MATERIAL / SAMPLE STORAGE 
Prostate biopsies taken will be stored by local site (NHS Trust) pathology departments. Blood 
and urine will be analysed / stored and disposed of as for all other clinical blood samples at 
local site (NHS Trust). Only members of the Trust's pathology staff have access to the samples. 
Patients will be consented to the possibility of stored biopsy samples being used for future 
research.  No blood will be stored longer than standard of care and will not be subject to 
future use.  Any future study involving use of the tissue samples for research would only be 
carried out with Research Ethical Approval by an Ethics Committee 
 

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5.10 SAFETY REPORTING (INTERVIEWS) 
It has been deemed unlikely by the study team that participants may be adversely affected 
by taking part in the interviews.  However, it is possible that as a result of taking part in the 
interviews participants may experience distress regarding their condition and the effect it has 
on their lives.  To ensure the study team become aware of this, participants will be provided 
with a contact card, which contains the contact details of the qualitative researcher to report 
any issues arising from taking part in the interview.  Any such contact made will be recorded 
on the adverse event form and reported to the PROSPECT trial management team, relevant 
R&D department and ethics committee (if deemed appropriate). Participants will also be 
directed to hospital based and independent support agencies as per local practice.  
 
5.11 PRESENTATION / DISSEMINATION OF RESULTS 
Real time data will be used throughout the duration of the study. Final results will be 
triangulated with other study data towards the end of the study and prepared for submission 
as part of the end of study report. 
  
5.12 INTEGRATED HEALTH ECONOMIC ANALYSES  
The aim of the economic analysis nested alongside the main trial uses the NHS perspective to 
determine the cost per QALYs (CUA), cost per PFS/FFS (CEA) and cost and consequences (CCA) 
to inform the decision regarding which interventions are most health-economically beneficial. 
Data on resource-use, FFS and quality-of-life (as measured by EQ-5D-5L) collected alongside 
the trial are used for the analysis. CRFs validated in the pilot study will be used to collect 
patient NHS resource usage. Alongside CUA and CEA we also propose the use of cost and 
consequences analysis to account for any important aspect of care that might emerge from 
the qualitative analysis and not captured via EQ-5D-5L or PFS/FFS (e.g. burden of treatment 
routine). A series of one-way, multi-way and probabilistic sensitivity analyses will be carried 
out to test the robustness of results.  
Alongside CUA and CEA we also propose the use of cost and consequences analysis to account 
for any important aspect of care that might emerge from the qualitative analysis and not 
captured via EQ-5D-5L or PFS/FFS (e.g. burden of treatment routine). A series of one-way, 
multi-way and probabilistic sensitivity analyses will be carried out to test the robustness of 
results. 
  
5.14 VISIT SCHEDULE  
5.14.1.PATIENTS (Main Study) 
The design and number of visits mirror the standard of care pathway for patients undergoing 
either focal therapy or radical therapy, so that additional patient burden is minimal.    

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Following enrolment, all patients will undergo a standard follow-up regimen in the cohort. If 
they undergo an MRI and biopsy, these usually occur within 6 months of enrolment under 
standard care. The results of these tests will be collated directly from patient records. If the 
patient has a cancer diagnosis then the biopsy laterality, Gleason grade and clinical and 
radiological stage details will be collated in the CRFs. Follow-up information (PSA blood tests, 
treatments given) will be collated from each follow-up visit directly from the patient records 
into CRFs. Specific treatment types (active surveillance, surgery, radiotherapy, minimally 
invasive therapies) or further diagnostic tests (MRI, biopsy) will be recorded into CRFs. 
Performance status will be collected. Further, patients will be sent out questionnaires asking 
about any prostate tests or treatments they might have undergone as well as patient reported 
outcome measures. The table below shows each participant’s schedule of activities. Data will 
be collected via the GP and/or hospital practices if necessary. 
NB - Once the primary outcome measures are reached (approx. 80 patients), the follow up 
period will be reduced to 3 months. 
 
* Collected if carried out in standard care practice 
Time window for each visit will be +/- 4 weeks 
By virtue of asking men to join PROSPECT prior to their investigation for prostate cancer we 
will have the consent of men who go on not to have prostate cancer.  We would still like to 
include these men in our cohort of patients.  The non-prostate cancer participants will provide 
valuable age and comorbidity matched control cohort to participants with prostate cancer.  
Many of these patients will receive repeat referrals for investigation of prostate cancer again 
in the future and as such it may be valuable to ask questions of this population in the future.  
They will receive questionnaires at the same intervals as men with prostate cancer. The 
inclusion and observation of men without prostate cancer in PROSPECT will also be valuable 
because it will afford us the opportunity to implement methods for the arrangement and 
follow-up of large numbers of patients.  For instance, fluidic or imaging biomarkers as 
alternative follow-up strategies for these men who might still harbour or develop cancer in 
 
Screening  
Baseline 
0-6 months  
6 Month intervals up to 24 
months (+/- 4 weeks) 
Informed Consent 
✓ 
 
 
 
PSA  
 
✓ 
 
✓ * 
 
Medical history (from 
medical records and 
questionnaires to 
patients) 
 
✓ 
✓  
MRI, biopsy 
Grade and 
stage if cancer 
✓  
Treatment given if cancer 
Other diagnostic tests carried 
out if not 
Quality of Life (QoL) 
Questionnaires sent 
directly to patients 
 
✓ 
✓ 
✓ 

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future.  These would be tested as randomised interventions in PROSPECT in the normal 
manner. 
An overall CONSORT flowchart for the PROSPECT cmRCT model and a flowchart 
demonstrating the potential for further embedded RCTs can be found in Appendix A  
 
5.14.2 PATIENTS (Qualitative Sub study) 
Face-to-face or remote semi-structured interviews will be performed in at least five men who 
agree to, and five who do not agree to a randomised intervention. As these are therefore 
dependent on the timing of that intervention, it could occur at any point in the trial. Whilst 
the aim is to interview five of each interview type, that is the minimum. We will continue to 
invite participants to interview until no further qualitative themes emerge from the 
interviews.  We will use purposive sampling to ensure our sample relates to the UK population 
in terms of wealth / income, ethnicity and age.  Men will continue to be approached for 
interview until the qualitative sample is representative of these factors. How the interviews 
are performed is outlined in section 6.8. 
 
 
 
 
 
 
 
 
5.14.3 HEALTHCARE PROFESSIONALS  
Healthcare professionals i.e. doctors and nurses, who are involved in prostate cancer care and 
research will be approached by the clinical trial coordinator by email to take part In PROPSECT 
by giving an interview as to their thoughts on the study design. Face-to-face or remote semi-
structured interviews that focus on ethics, implementation, practicality and efficiency of 
PROSPECT will be performed of at least 5 but up to 10 doctors and nurses and up to 5 research 
and managerial staff involved in prostate cancer care and research. We will use purposive 
sampling to ensure our sample relates to the direct healthcare workforce for urological 
oncology, in terms of appropriate spread for age and job type.  Healthcare professionals will 
continue to be approached for interview until the qualitative sample is representative of 
these factors. We will conduct interviews at 6 and 12 months from the opening of PROSPECT.  
There will be a different Interview Questionnaire Template for interviews with healthcare 
professionals. We will continue to invite participants to interview until no further qualitative 
 
Screening 
At randomisation 
Informed Consent  
✓ 
 
Semi-structured 
interview (Entry) 
 
✓ 
Semi-structured 
interview (Exit) 
 
✓ 

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themes emerge from the interviews.  How the interviews are performed is outlined in section 
6.8. 
 
 
 
 
 
 
 
6 NON-TREATMENT STUDY INTERVENTIONS 
6.1 INFORMED CONSENT PROCEDURE 
Informed consent may be taken via the traditional paper-based approach or via electronic 
methods through the REDCap database for seeking, confirming and documenting informed 
consent. 
It is the responsibility of the Investigator, who may be a medical or nursing professional, or a 
clinical research practitioner, but who must be GCP certified to obtain written or electronic 
informed consent from each patient prior to participation in the study. This follows adequate 
explanation of the aims, methods, anticipated benefits and possible risks of the study. A 
minimum of 24 hours must be given for consideration by the patients before taking part. The 
researcher must record when the PIS has been given to the patient. It must be explained to 
the patient that they are in no manner obligated to take part in the study and further, that 
they may withdraw at any time during the study and are not required to give a reason for 
doing so. No clinical study procedures may be performed prior to obtaining written or 
electronic informed consent from the participant. Consent is not a denotation of enrolment 
into the study. A copy of the signed ICF must be given to the patient for their records. If paper-
based consent has been taken, the original form with the wet signature will be retained at 
the study site. If consent has been taken remotely, a printed copy of the completed document 
must be retained at site. A copy of the completed informed consent must also be placed in 
the patients’ medical notes. If at any time during the study new safety information results in 
significant changes in the risk/benefit assessment, the consent form is to be reviewed and 
updated as necessary and if appropriate, patient will be consented again. Patients will be 
consented to provide their full contact details including name, address and email address 
where appropriate to the trial team based at Imperial so that the trials team can send out 
PROMS and questionnaires on health status.  
 
6.2 DOCUMENTATION OF SCREEN FAILURES 
 
Trial 
Commence
ment 
6 Months 
12 Months 
Informed Consent  
✓ 
 
 
Semi-structured 
interview  
 
✓ 
✓ 

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A screening log will include information on all patients who have voluntarily given informed 
consent to participate in the study and whether or not the patient was then enrolled. The 
screening log will include the patient initials, date of birth, the date of signing the ICF, and, if 
failed screening, the reasons why. 
6.3 DEMOGRAPHICS, MEDICAL AND UROLOGICAL HISTORY 
A complete medical and urological history will be obtained at the Screening visit. 
Demographic information will include date of birth and ethnicity. All patients in this study are 
men. Medical history will include, and significant prior and concurrent conditions, diseases 
and procedures not related to urology. Urological history will include all conditions and 
procedures related to urology. The World Health Organisation performance status will also 
be documented. 
 
6.4 LABORATORY TESTS 
Biologic assessment will include blood tests, as drawn by venipuncture, including:  
• Prostate specific antigen (PSA), a test often used to screen for prostate cancer but 
used here as a surrogate objective marker of tumour load. 
 
6.5 MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING (mpMRI) 
MpMRI will be performed with either 1.5 or 3.0 Tesla scanners with a pelvic phased array coil. 
The patient will be supine and contrast administered by use of a power injector. As per 
consensus guidelines setting out minimum requirements, T2-weighted, diffusion-weighted 
(DWI), +/- dynamic contrast enhanced (DCE) sequences (Intravenous Gadolinium) will 
acquired. The images will be reported by a dedicated specialist uro-radiologist.   
 
6.6 PROSTATE BIOPSY 
In participants in which a lesion scoring 3-5 is identified a transperineal or transrectal targeted 
biopsy with concomitant systematic biopsies will be performed and performed by operators 
experienced in each approach.  
 
6.7 VALIDATED PATIENT QUESTIONNAIRES 
International Prostatic Symptoms Score (IPSS) a validated questionnaire made up of seven 
questions to ascertain the severity of lower urinary tract symptoms. [54] 
EPIC bowel and bladder questionnaire (EPIC-26), a validated questionnaire used to measure 
urinary incontinence, urinary irritation, bowel, sexual and hormonal health related quality of 
life. [55]  

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IIEF-5, a validated, multi-dimensional, self-administered investigation that has been found 
useful in the clinical assessment of erectile dysfunction and clinical trials [56] 
The EuroQol (EQ-5D-5L) will be used in the study as a generic measure of health-related 
quality-of-life which can be linked to public preferences. [57] 
7 FOLLOW-UP 
7.1 SCHEDULE OUTLINE 
Follow-up will not be dictated by the study within the cohort. It will be standard of care for 
that patient. This will differ, as some will have no cancer, some have cancer treated whilst 
others will have surveillance for low risk cancer. Clinical outcomes such as presence or 
absence of cancer on biopsy, TNM stage, risk, grade and type of treatment with any future 
failure and adjuvant/salvage treatment will be recorded. Those not having a cancer diagnosis 
will have future tests and outcomes and future prostate cancer diagnosis recorded if 
appropriate. Health status and PROMs will be collected at regular intervals during study 
duration. 
 
7.2 PATIENT RELATED OUTCOME MEASURES (PROMS) 
The PROMS as described in 6.7 will be used. Questionnaires should be self-administered, 
although it is recommended that a key person (e.g. research nurse) at each centre be 
responsible for the data collection to optimise compliance and completeness of the data.  
The patients should complete the quality of life and the resource use data questionnaires 
independently without discussion with friends or relatives and all questions should be 
answered. The member of the study team should check each questionnaire and query any 
missing or incorrect data with the patient. Checks should also take place for date and 
identifiers. Patients should be approached at appropriate visits to complete the 
questionnaires.  
 
7.3 FOLLOW-UP CONSULTATIONS 
Collection of data at each time point will be permissible via postal, electronic, remote or face-
to-face communication. Unless the patient requests face-to-face visits they will only require 
attendance for hospitals visits that are defined by the local hospitals follow-up protocol within 
standard care.  In certain circumstances it may be appropriate to replace hospital visits with 
telephone, remote or email consultations providing that it is still possible to collect all the 
necessary follow-up information. In order to maintain confidentiality during email 
consultations these episodes will be conducted via the local site practitioner’s protected NHS 
email account. Such remote consultations are undertaken frequently in routine clinical care 
and in these instances, it is acceptable to perform appointments with telephone, remote  or 
email consultations providing the required blood results, such as PSA tests are available to 
the research team (can be performed at local hospital or GP practice as per patients request 
and the GP’s discretion). In any instance the hospital will carry out these tests if the GP was 

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to refuse. All necessary information required to complete the follow-up case report form 
(CRF) is still required. All details on the telehealth consultations must be recorded in the 
patients’ notes. 
 
7.4 STUDY VISITS – SPECIFIC TESTS 
7.4.1 PROSTATE SPECIFIC ANTIGEN (PSA) 
Blood sample for PSA can be collected during a scheduled hospital visit or at a hospital local 
to the patient or at a community/primary care facility, whichever is more convenient for the 
patient provided the result is available to the research team.  
 
 
7.4.2 PATIENT RELATED OUTCOME MEASURES (PROMS) 
PROMS questionnaires can be completed or returned during a scheduled hospital visit or via 
post/electronic communication.  
 
7.4.3 FURTHER FOLLOW-UP IMAGING 
Follow-up imaging will not be protocol led, with appropriate imaging chosen as per the local 
hospital resources and policies (may include any of prostate MRI, nuclear medicine bone scan, 
PET-CT/MRI, Whole body MRI or CT chest/abdomen/pelvis). 
 
7.4.4 FURTHER FOLLOW-UP BIOPSIES 
Some patients will undergo further biopsies due to ongoing suspicion of cancer or following 
treatment as part of their standard care.  
 
7.4.5 FURTHER NON-TRIAL INTERVENTIONS 
Some patients will also undergo secondary non-cancer related procedures to manage adverse 
events from the therapy such as, but not limited to, transurethral resection of prostate, 
bladder neck incision, urethral dilatation, optical urethrotomy, male-sling or other continence 
procedures as well as penile implant surgery for impotence. Endoscopic tests or interventions 
of the lower bowel may also be required. These rates of interventions will be collected. 
 
7.4.6 FUTURE FOLLOW-UP 

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Patients will be consented for their names to be linked to national registries for survival 
information such as NHS Information Centre/Office of National Statistics (ONS) in 
England/Wales and General Register Office in Scotland, Hospital Episode Statistics (HES). 
 
7.5 LABORATORY EVALUATIONS  
7.5.1 BLOOD TESTS:  
PSA will be measured as per standard care and using local laboratory processes and assays. 
Centralised measure of PSA will not be used. No additional haematology or biochemistry tests 
will be mandated by the trial. It is envisaged that standard of care haematological and 
biochemical tests will be ordered by the treating clinician to monitor for pre-assessment 
requirements for anaesthetic fitness or for assessing treatment related toxicity.  
 
7.5.2 URINALYSIS:  
No additional urinalysis test will be mandated by the trial. 
 
7.6. SAMPLE STORAGE AND ANALYSIS 
7.6.1 STANDARD OF CARE SAMPLES 
The standard care urine samples taken as part of routine clinical care 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.  
Blood for standard care tests in clinical care will be via peripheral venepuncture and placed 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.  
 
7.6.3 HEALTH STATUS 
At the screening visit, patients will also be asked to give optional consent for identifiable data 
to be linked with the national databases (ONS and HES database). The identifiable fields (NHS 
number) required for linkage will be encrypted using a one-way encryption algorithm. We will 
ask patients if they are happy to give consent for their health status to be followed up over 
time. This will be done by linking the patient’s name and NHS number with records held by 
the NHS and maintained by the NHS Information Centre and the NHS Central Register, or any 
applicable NHS information system. This will allow us to track what happens after the study 
finishes and observe if anyone gets cancer in future and about the type of cancer and the 
treatment they have had.  

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We will also ask patients whether or not they give permission to be contacted by a member 
of the central / local study research team within 10 years of signing their consent form, after 
the study has ended to assess their willingness to complete a questionnaire about their health 
status (including details of any other tests and treatment they have had since the study) and 
quality of life. If the patient decides to take part a member of the study research team may 
send this request to the patient’s home address. This will only occur if the trial progresses to 
main phase. 
As prostate cancer is often a slow-growing disease which may not progress for many years we 
will also ask patients if they are happy to keep personal data be stored or accessed for an 
additional 10 years on the NHSCR (National Health Service Care Register). This is an optional 
part of consent. 
 
8 STUDY COMPLIANCE AND PARTICIPANT WITHDRAWAL 
8.1 PARTICIPANT WITHDRAWAL FROM STUDY 
Withdrawal from the study refers to discontinuation of study treatment and study procedures 
and can occur for the following reasons: 
• Subject decision 
• Loss to follow-up 
Withdrawal of patients from the cohort is an important outcome in itself for PROSPECT to 
evaluate the acceptability of the study structure and design to participants.   
Men may decide to opt out of PROSPECT at any time.  This is entirely within their right to 
do so.  Such cases will be reported to the Research Team Office so that no further data are 
entered onto the database, as specified in the patient information leaflet and appropriate 
Standard Operating procedure.  Data captured before consent was withdrawn will be used 
in the study, but no further data, beyond this date will be collected or used in any analysis.  
The right to opt out of PROSPECT at any point, without reason and with no effect on the 
treatment received by the patient will be made clear to men in the PIS.   
It is the patient’s 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.  This will also be made clear in the Patient 
Information Sheet and in the Informed Consent Form. It will be very helpful for the 
investigators to know the reasons men who decide to withdraw from the trial have for their 
decision.  We will ask these patients who request to opt out of the cohort whether they would 
consent to an interview with one of the researchers to investigate the reasons behind their 
withdrawal. We will make it clear to patients who withdraw from the study that their medical 
records will no longer be used for data collection. 
 
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Efforts should be made to maintain the study schedule and continue follow-up.   If a patient 
moves out of the geographical area of the cohort the patient will still be able to complete the 
health and quality of life questionnaires. Important clinical and follow-up details such as 
biochemistry, treatment modality, mortality can be sought by direct request of the 
researchers from the patient’s treating urology team, GP and by correlation with national 
registries. 
 
8.3 NON_RESPONDERS TO PATIENT QUESTIONNAIRES AND ATTEMPTS TO OBTAIN UP TO 
DATE INFORMATION ON PARTICIPANTS 
Completeness of data and patient questionnaire response rates is an important outcome in 
PROSPECT as it informs our analysis of feasibility.  Where possible we will prompt men to 
complete the questionnaires sent to them by telephone reminder or by email which will be 
coordinated by the Lead Investigator and Recruitment Officer at the respective participating 
centres. If a patient continues to not return or complete the QoL and symptom questionnaires 
sent to him, efforts will be made to contact the patient via telephone and by email in order 
to encourage the patient to respond.  The researchers at the participating centres may also 
co-ordinate with the departmental clinic appointments in order to hand the questionnaires 
to the patient personally. 
In the case of the study moving to its main phase, patients who do not complete the 
questionnaires for five consecutive years will no longer receive communication from the 
PROSPECT research team.  However, in the absence of a direct request from the participant 
to be removed from PROSPECT, the research group will continue to collect and store 
information pertaining to the individual’s health and prostate cancer status. 
 
8.4 PROCEDURES FOR PARTICIPANT WITHDRAWAL FROM STUDY 
Every effort should be made to follow-up all patients who have been randomised. Patients 
should, if possible, remain under the care of an oncologist or urologist for the duration of the 
trial. If care of a patient is returned to the GP, it is the responsibility of the responsible clinician 
who obtained the patient’s consent to participate in the trial to ensure that all relevant data 
collection forms are completed. Nurse-led follow-up is permitted and should be conducted in 
line with local practice and procedures. 
If the patient moves away from the local area, arrangements should be made for trial follow-
up to be undertaken by their new local centre. Details of other participating centres can be 
obtained from the Study Manager. If the responsible clinician moves, appropriate 
arrangements should be made to arrange for trial follow-up to continue at the centre.  
All efforts should be made to preserve the patient’s initial consent for long-term survival 
information to be flagged through national registries, for example NHS Digital (previously the 
Health and Social Care Information Centre); Office of National Statistics (ONS) in 
England/Wales; General Register Office in Scotland; Hospital Episode Statistics (HES) or Public 
Health England.  

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In order to do this, we will provide all patients an optional consent to provide identifiable 
information for us to trace the patient on the National Health Service Care Register (NHSCR) 
for an additional 10 years. 
We will also ask patients whether or not they give permission to be contacted by a member 
of the study research team within 10 years of signing their consent form, after the study has 
ended to assess their willingness to complete a questionnaire on their health status and 
quality of life. This will allow us to track what happens after the study finishes to observe if 
anyone gets cancer in future and about the type of cancer and the treatment they have had. 
Results of the optional health status check will also help us to refer to any future upcoming 
studies. If the study does not continue after the pilot, each patient will be contacted and 
informed as such when the study ends. 
 
9 PHARMACOVIGILANCE/ ADVERSE EVENT REPORTING 
The Common Terminology Criteria for Adverse Events (CTCAEv4.0) will be used to report 
adverse events. Please refer to for further details: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Qui
ck_Reference_8.5x11.pdf 
 
9.1 ADVERSE EVENT (AE) 
An AE is any untoward medical occurrence in a patient or clinical trial subject undergoing a 
trial intervention and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
trial interventions, whether or not considered related to the interventions being evaluated. 
 
9.1.1 ADVERSE EVENT RECORDING 
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. All AEs and 
SAEs will be recorded throughout the study and all SAES should be reported to the sponsor. 
Any unexpected and related SAES should also be reported to the REC (as per attached RGIT 
SOP – appendix 3). 
 
9.1.2 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 

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9.1.3 CAUSALITY OF ADVERSE EVENTS 
• 
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 trial interventions). 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 administration of the trial interventions). 
However, the influence of other factors may have contributed to the event (e.g. the patient’s 
clinical condition, other concomitant treatments). 
• 
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. 
 
9.1.4 ABNORMAL LABORATORY TEST RESULTS 
All clinically important abnormal laboratory test results (apart from PSA) occurring in 
participants will be recorded as adverse events. The clinically important laboratory tests will 
be repeated at appropriate intervals until they return either to baseline or to a level deemed 
acceptable by the investigator and the clinical monitor, or until a diagnosis that explains them 
is made. 
 
9.2 SERIOUS ADVERSE EVENTS (SAE) 
9.2.1 DEFINITION OF SAE 
An SAE is defined as any event that: 
• 
Results in death;  
• 
Is life-threatening*; 
• 
Requires hospitalisation or prolongation of existing inpatient 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. 

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** “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. 
 
9.2.2 LIST OF EXPECTED ADVERSE EVENTS: 
There are number of expected potential adverse events after interventions that may occur 
and require hospitalisation but will not require reporting as SAEs but will be collected. These 
include: 
• 
Urinary retention and any admission required for this 
• 
Urinary tract infection and any admission required for this 
• 
Epididymo-orchitis and any admission required for this 
• 
Dysuria 
• 
Debris in urine and any admission required for this 
• 
Haematuria and any admission required for this 
• 
Erectile dysfunction and any other sexual sequelae side-effects such as dry orgasm, 
lack of orgasm, poor libido 
• 
Urinary incontinence 
• 
Rectal discomfort, bleeding, diarrhoea 
• 
Recto-urethral fistula and any operations required for this 
• 
Lethargy, tiredness, poor appetite 
• 
Urethral stricture and any operations required for this 
• 
Transurethral resection of prostate and any operations required for this 
• 
Operations required for symptoms of bladder outlet obstruction 
• 
Any expected complication related to post-operative course from radical 
prostatectomy i.e. lymphocoele, bowel injury, haematoma needing percutaneous drainage  
• 
Expected toxicity from systemic therapy such as neutropenia, neutropenic sepsis, 
weight gain, decreased libido, breast tenderness, metabolic syndrome, lethargy, fatigue, 
osteoporosis, nausea and vomiting, diarrhoea, constipation, muscle/joint pains and hair loss. 

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• 
Bowel stricture post radiotherapy, and procedures required for this 
 
9.2.3 REPORTING OF SAEs 
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 study related, 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/electronic case report form [RedCap]).  
 
9.2.4 RELATED SAEs 
Related: results from administration of any research procedures 
 
 9.2.5 UNEXPECTED SAEs 
Unexpected: type of event is not listed in the protocol as an expected occurrence 
  
9.2.6 REPORTING OF SAEs THAT ARE RELATED AND UNEXPECTED 
An SAE form should be completed on the Redcap eCRF within 24 hours. However, relapse, 
death and/or hospitalisations for elective treatment of a pre-existing condition do not need 
reporting as SAEs. 
All SAEs should be reported to the 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 of sponsor for reporting SAEs are as follows: 

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Research Governance and Integrity Team (RGIT): 
Imperial College London and Imperial College Healthcare NHS Trust 
E-mail: rgit@imperial.ac.uk 
  
Chief Investigator: 
Professor Hashim Uddin Ahmed 
Imperial College London, Charing Cross Campus 
E-mail: hashim.ahmed@imperial.ac.uk or prospect@imperial.ac.uk 
Tel: 020 7589 5111 (Mon to Fri 09.00 –17.00) 
 
9.3 ANNUAL PROGRESS REPORTS  
Annual Progress Reports will be submitted to the Research Ethics Committee, the Regulatory 
Authority and the Sponsor in accordance with local requirements. The Annual Progress 
Reports will detail all SAEs recorded. 
 
9.4 PREGNANCY 
Not applicable as the study population is male. 
 
9.5 CHILDREN 
Not applicable as the study population is over 18 years of age. 
 
9.6 REPORTING URGENT SAFETY MEASURES 
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 and give written notice to the HRA, 
the relevant research ethics committee (REC) as well as the sponsors of the measures taken 
and the circumstances giving rise to those measures. The sponsor in any case should also be 
informed of urgent safety measures. 
10. STATISTICAL ANALYSES 
10.1 SAMPLE SIZE AND POWER CONSIDERATIONS 
Acceptability to initial consent sample size 

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We will measure the precision around a conservative 30% anticipated acceptance to 
participate in the study. 
80 patients are needed to show that 30% (95% CI of ±10%) of the eligible patients will accept 
initial consent with a 95% CI of ±10%, assuming 5% loss to follow up. 
 
10.2 PLANNED RECRUITMENT RATE 
We propose to recruit to PROSPECT over 18 months with each man followed for at least 6 
months within the current funding envelope.  The study may be extended if further 
funding is awarded and this will require approval by REC. We estimate that each 
participating centre receives 15-20 new referrals for assessment of possible prostate 
cancer each month.  Therefore, we estimate that 180-250 men will be approached to 
consider entering PROSPECT a year per centre. The actual cohort sample will not be 
restricted as the overall number needed will be dependent on future randomised 
interventions and therefore there is no maximum number. if the feasibility number is met 
then we will continue recruitment for the entire recruitment period with no upper limit 
on numbers and continue beyond existing recruitment period if further funding allows and 
pending formal REC approval. 
 
10.3 STATISTICAL ANALYSIS 
As outlined in section 5.7 we wish to assess the acceptability and feasibility of this trial design 
in men undergoing evaluating and subsequently potentially being treated for prostate cancer 
and other benign disease of the prostate.  We will be testing the acceptability of the trial 
format to patients as well as the levels of data return and the quality of data return.  As such, 
for these endpoints we have no formal power calculations for the qualitative aspects.  
As part of the feasibility objectives, we will measure the numbers of men approached and 
numbers saying yes to each point of consent. We will measure the precision around our 
estimate of 30% acceptance to the first point of consent. 
All the statistical analyses will be outlined in a Statistical Analysis Plan (SAP) which will be 
signed by the CI, Senior Statistician and TSC ahead of seeing the data. 
 
 

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11. REGULATORY, ETHICAL AND LEGAL ISSUES 
11.1 DECLARATION OF HELSINKI 
The investigator will ensure that this study is conducted in full conformity with the 7th 
revision of the 1964 Declaration of Helsinki. 
 
11.2 GOOD CLINICAL PRACTICE  
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). 
 
11.3 CLINICAL TRIALS AUTHORISATION 
Not applicable as cohort study and not CTIMP. 
 
11.4 INDEPENDENT ETHICS COMMITTEE APPROVAL  
11.4.1 INITIAL APPROVAL 
Prior to the enrolment of subjects, the Research Ethics Committee (REC) and Human Research 
Authority (HRA) must provide written approval of the conduct of the study at named sites, 
the protocol and any amendments, the Patient 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.  
 
11.4.2 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 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. 
 
11.4.3 ANNUAL PROGRESS REPORTS AND END OF TRIAL NOTIFICATION 
The REC will be sent annual progress reports in accordance with national requirements and 
will also be informed about the end of the trial, within the required timelines. 
 

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11.5 HRA APPROVAL 
Health Research Authority (HRA) approval will be obtained prior to starting the study.  
The HRA also needs to be notified of all protocol amendments. 
 
11.6 OTHER REQUIRED APPROVALS 
PROSPECT itself requires no additional approvals for the cohort element. Further approvals 
may be necessary, dependant on interventions offered after point of consent 2. As 
appropriate, the Chief Investigator will ensure that the procedures are compliant with 
regulatory bodies. 
 
11.7 NON-COMPLIANCE AND SERIOUS BREACHES  
All protocol deviations and protocol violations will be reported via the eCRF 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 HRA and REC 
within 7 days of becoming aware of the serious breach. 
 
11.9 INSURANCE AND INDEMNITY AND SPONSOR 
11.9.1 INDEMNITY  
Imperial College London holds negligent harm and non-negligent harm insurance policies which apply 
to this study.  
 

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11.9.2 SPONSOR  
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.  
 
11.9.3 FUNDING 
 Wellcome trust are funding this study.  
 
11.10 TRIAL REGISTRATION 
The study will be registered on the trial database ClinicalTrials.gov in accordance with 
requirements of the International Committee of Medical Journal Editors (ICMJE) regulations. 
 
11.11 INFORMED CONSENT 
All subjects must sign and personally date the REC approved Informed Consent Form after 
having received detailed written and verbal information about the reason, nature and 
possible risks associated with the research study.  This will apply for both our initial 
invitation to participate in the PROSPECT cmRCT, and any subsequent intervention(s) we 
seek to evaluate by inviting cohort participants to undergo.  PROSPECT will be the first 
time that the cmRCT design has been piloted for the evaluation of interventions in the 
prostate pathway.  Although the trial design is no longer controversial given its 
increasingly widespread adoption by clinical researchers worldwide in benign and cancer 
disease spaces as well as complex interventions, the innovative features of the cmRCT 
design warrants further consideration of its specific ethical matters.   
 
11.11.1 Patient information about future interventions at Point of Consent 1 
The Patient Information Sheet and the Consent Form should not need to include details 
on the proposed interventions to which the patient may be randomly selected in the 
future.  This is what other ethics committee approved studies have done and the reasons 
are listed below.  
• The exact disease status and risk of a disease once diagnosed are not known at the 
first point of consent for a man. 
• It is not possible to provide information on all of the possible interventions that might 
be evaluated that a man may be invited to participate in because we do not yet know 
what they all are.  Further treatments may become available in the future which we 
are not currently able to predict and inform the patient about. 
• To give prospective participants information about all the possible novel interventions 

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or changes in management for evaluation as embedded randomised interventions to 
which they may or may not be randomly selected may represent excessive information 
for the patient.  The idea of ‘patient-centred consent’ is central to the attribute of the 
cmRCT.  Therefore, we would not like to provide patients who we are seeking to recruit 
to the cohort an excess of information on all possible future interventions as we do 
not want to overwhelm them, potentially causing confusion and thereby reducing 
recruitment rates. 
• Point of Consent 1 gains consent only to collect patient information prospectively and the 
permission to re-contact in the future if they are eligible for an intervention.  PROSPECT 
participants categorically cannot undergo any embedded novel interventions or changes 
in management strategies for evaluation without being approached again by the 
researchers at Point of Consent 2.  The consent process at Point of Consent 2 will be in a 
patient-centred manner that will include comprehensive information on the risks and 
benefits of the intervention in question. So that the procedure is clear to the patient who 
will undergo the intervention if he agrees to it.   
• The principle of consent-for-consent in which patients are asked to consent to a future 
approach to participate in research (which in itself is subject to further patient information 
and informed consent) is now being used in a number of disease areas and networks (e.g., 
DH funded DCRIS; BioResource funded by NIHR).  
• The level of information that is given to men in the cohort is not yet defined.  As this 
protocol also seeks to assess the acceptability and feasibility of the cmRCT design we will 
interview patients and healthcare professionals to determine the level of information that 
should be given to patients at Point of Consent One as part of our qualitative work. We 
will change our patient documentation, subject to substantial amendments, if necessary 
based on this qualitative work. 
 
11.11.2 Participants Consented for possibility of future intervention who are not 
approached for embedded randomised studies 
All PROSPECT participants will have been consented at Point of Consent 1 for the 
possibility of being selected in the future for an intervention.  Many of these men will not 
be invited to participate in embedded randomised studies.  
• Through the consent process and the PIS we will make clear the structure of the 
PROSPECT cmRCT, such that participants are aware that they may might not be 
approached for an embedded intervention as they may be ineligible for interventions 
being trialled, or they may be eligible but not approached due to the randomized 
process.  
• Through the consent process and the PIS we will make clear that the treatments and 
interventions being trialled are not of proven benefit to patients. This is why we as 
researchers are seeking information on the embedded interventions.  Interventions 
trialled within the cmRCT format should only be interventions around which there is 
clinical equipoise. Therefore, it must be clear to patients that the usual care 

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management and treatment they receive will under no circumstances be sub-optimal 
or compromised as a result of their participation in PROSPECT within the longitudinal 
cohort element of the study.   
• Through the consent process and the PIS we will make clear that patients who are not 
selected to embedded randomised interventions in PROSPECT will continue to 
experience the standard of care management according to their treating doctors and 
multi-disciplinary medical team. 
• Patients in our focus groups emphasised the fact that participation in the cohort was 
something in of itself that they might derive benefit from. For instance, access to 
researchers and additional patient reported outcome measures reporting, and that 
such participation might help others through outcomes measures that might not 
otherwise be collected and reported. 
The right of the patient to refuse to participate in the study without giving reasons must 
be respected.  After the patient has entered the study, the clinician must remain free to 
manage the patient however s/he feels fit to suit the best interest of the patient, 
regardless of the protocol.  
An Independent Ethics Committee must approve the protocol, the patient information 
sheet, the content of the informed consent form and any promotional materials used for 
the recruitment of subjects before the accrual of any patients. If legally required, the 
protocol and informed consent must be submitted to the country regulatory authorities 
Participants should be made aware and agree that their personal information may be 
scrutinised during monitoring and audit by competent authorities and properly authorised 
persons. However, the personal information will be treated as strictly confidential and will 
not be publicly available.  
 
11.12 CONTACT WITH GENERAL PRACTITIONER  
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. 
Every six months, the trial management team or investigator will contact each participant’s 
General practitioner for updates on the participant’s medical or procedural history, as well as 
any changes to the participant’s regular medications.  Full informed consent from each 
participant will be required for this. 
 
11.13 PARTICIPANT CONFIDENTIALTY 
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 

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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 documents for the 
purposes of monitoring, auditing, or inspection by the Sponsor, authorised representatives of 
the Sponsor, NHS and regulatory authorities. 
For trial follow-up purposes, the trial management team are required to contact each 
participant every six months. To allow for this, the team will require the names, addresses - 
and email address where applicable – of each participant. These details, i.e., the names 
address and email address will be housed separately to the electronic CRF and 
pseudonymised, i.e., linked by the participant’s unique trial identifier and will be stored, 
securely walled off on Imperial College London University computers with access only granted 
to the study research team. 
 
11.14 DATA PROTECTION  
The investigator will preserve the confidentiality of all participants taking part in the study, 
which will be conducted in accordance with GDPR and the Data Protection Act 2018. 
Furthermore, all investigators and study staff must comply with the requirements of the Data 
Protection Act with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. 
 
11.15 END OF TRIAL 
The end of the trial will occur at the point of database lock or at the request of the Trial 
Steering Committee. 
 
12. DATA MANAGEMENT, STUDY DOCUMENTATION AND DATA STORAGE 
12.1 PERSONAL IDENTIFYING DATA: 
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.  
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 this 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 

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explicit consent for data transfer. Data within the NHS system such as patient notes, and 
reports will remain confidential in accordance with NHS confidentiality code of practice.  
Personal identifying data will be kept electronically on NHS computers at participating sites 
and in paper format stored in NHS premises within secure offices only accessible by 
authorised trained personnel. The central research team will also keep patient identifiable 
names and contact details separate from the main trial database and linked with trial 
identifiers in order to send health status questionnaires and PROMS directly to patients in the 
post or via email or online links via the RedCap eCRF database.  
 
12.2 REDCAP ELECTRONIC CASE REPORT FORM DATABASE: 
Database Data and remote informed consent will be entered onto a trial database application 
electronic Case Report Form (eCRF) known as RedCap. E-consent will be documented using 
eSignatures traced with a finger, mouse or a stylus.  
The database is stored on an Imperial College network protected by a firewall. Access to the 
database is restricted to the research team by login and password for user. All RedCap users 
will be trained and certified in the usage of the database. Desktop security is maintained 
through user names and frequently update passwords. On this eCRF or other documents 
submitted to the coordinating centre or sponsor, documents will not be labelled with any 
patient identifiable information, but instead by a unique patient identification number (study 
number). Therefore all identifying information will be removed. 
 
12.3 SITE FILES AND SOURCE DATA: 
The investigator at each participating site must ensure that patients' anonymity will be 
maintained and that their identities are protected from unauthorised parties. Manual files of 
source data and consent forms will be stored at each participating centre. This will also 
include the Investigator Site File (ISF), which will all be locked and secured in filing cabinets or 
rooms only accessed by authorised personnel. 
 
12.4 TRIAL MASTER FILES (TMF): 
This will be kept in a secured, locked Imperial College Office space in the Laboratory block at 
Charing Cross Hospital accessed only by appropriately trained study staff, people working on 
behalf of the Sponsor, and by representatives of Regulatory Authorities, where it is relevant 
to this research. 
Storage and handling of confidential trial data and documents will be in accordance with 
GDPR and the Data Protection Act 2018 (UK). Embedded qualitative sub-study data: 
 
 

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12.5 QUALITATIVE SUBSTUDY DATA: 
Qualitative data will be stored at Imperial College London and stored separately from 
recordings, transcripts and data analysis notes. A laptop may be used to store data 
temporarily when conducting fieldwork, but any data will be transferred securely, using an 
encrypted USB stick to a Imperial College PC and information held on the laptop and USB stick 
will be deleted. This will be recorded in data management records stored within the study 
site file. The laptop will be password protected and all files and documents pertaining to the 
study will also be password protected. All hard-copy data and study information will be kept 
secured in locked filing cabinets within Imperial College. All electronic data will be kept 
securely on a password protected computer and files and folders will also be password 
protected. Electronic files will be held on a University secured server. Only research staff will 
have access to the secure drive. Digital audio recordings of interviews will be uploaded to the 
secure drive at Imperial College and the originals deleted from the digital recorder. Audio 
recordings will be kept in a separate folder to any transcripts. Once transcribed and checked, 
interview transcripts will be stored in PDF format on the secured drive, which will ensure 
content cannot be altered. All transcripts will have identifiable information removed. 
Transcripts will be prepared in house and uploaded to the NVivo 11 qualitative software 
programme for efficient and rigorous data management. Anonymised transcripts will be 
stored securely for 10 years. No data will be transferred outside the EU. 
 
12.6 VOICE RECORDINGS: 
All voice data will be deleted after checking transcription accuracy. Anonymised transcripts 
will be stored securely for 10 years on secure Imperial College London computers. No data 
will be transferred outside the UK.  
 
12.7 DESTRUCTION OF STUDY DOCUMENTS: 
The investigator must retain essential documents until notified by the Sponsor, and for at 
least 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 at a later 
date. Consideration should be given to security and environmental risks. 
No study documents 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. 
 
 
 

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12.1 SOURCE DATA 
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 the 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.  
 
13.2 LANGUAGE 
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. 
 
13.3 DATABASE 
The principal means of data collection from participant visits will be Electronic Data Capture 
(EDC) via the internet using the an eCRF database.  Data is entered into the EDC system via 
site personnel.  All source data will be recorded in the CRF and the completed case report 
book will be signed by the Investigator or his/her appropriate designee.  All changes made at 
any time following the electronic signing will have an electronic audit trail with a signature 
and date. The completed case report book will then again be signed by the investigator or 
his/her appropriate designee. Specific instructions and further details will be outlined in the 
CRF manual.  
 
13.4 DATA COLLECTION 
All study data will be entered into electronic Case Report (eCRFs) in a database provided by 
the Sponsor. All eCRFs will be completed using de-identified data.  

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CRF completion may be delegated by the Principal Investigator (documented on the 
Delegated Task List) to other study personnel though the Principal Investigator remains 
responsible for the accuracy and integrity 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 for creation, 
modification, maintenance and archiving of source data via any computerised systems will be 
provided in the study specific Data Management Plan (CRF manual).  
 
13.5 ARCHIVING 
All trial documentation, including that held at participating sites and the trial coordinating 
centre, will be archived for a minimum of 10 years following the end of the study. 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). 
 
14. STUDY MANAGEMENT STRUCTURE  
14.1 TRIAL STEERING COMMITTEE (TSC)  
A combined Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) has been 
convened and included as a minimum an Independent Chair, Independent Clinician, 
Independent Statistician, and Patient Representative. The role of the TSC/DMC is to provide 
overall supervision of trial conduct and progress. Details of membership, responsibilities and 
frequency of meetings will be defined in a separate Charter. 
 
14.2 TRIAL MANAGEMENT GROUP (TMG) 
A Trial Management Group (TMG) will be convened including the Chief Investigator (co-chair), 
lead co-investigator (co-chair) and other co-investigators and key collaborators, Study 
Coordinator, Study Statistician, Operations Manager and Study Manager. The TMG will be 
responsible for day-to-day conduct of the trial and operational issues. Details of membership, 
responsibilities and frequency of meetings will be defined in separate Terms of Reference. 

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When necessary, decisions will be referred to the TSC/DMC. Meetings will be scheduled in a 
risk-adapted manner to allow for the review of events during the trial.  
 
14.3 DATA MONITORING COMMITTEE (DMC)  
As mentioned in section 14.1, the DMC is combined with the TSC. 
 
14.4 EARLY DISCONTINUATION OF THE STUDY 
In case of early discontinuation of the study, the Follow-up Visit assessments should be 
performed for each subject, as far as possible. 
 
14.5 RISK ASSESSMENT 
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. 
 
14.6 MONITORING 
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, 
developed in accordance with the risk assessment. 
 
14.7 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality Control will be performed according to ICTU 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 UK Policy Framework for Health and Social Care (2nd Edition).  
 
 
14.8 PEER REVIEW 

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This study has been peer reviewed by the funder Wellcome Trust and within the Urology 
Department at Imperial College London. It has also undergone review by the NCRI (UK) 
Prostate Clinical Studies Group. 
 
14.9 PATIENT AND PUBLIC INVOLVEMENT 
Lay people (including those who have undergone treatment for prostate cancer) have been 
involved in the design of the study, and will participate in the management of the research, 
and analysis and dissemination of the findings. This has been detailed in the introduction to 
the protocol. 
 
 14.10 PUBLICATION AND DISSEMINATION POLICY 
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 in connection with the development of the ablative or radiotherapy or surgical 
techniques and, therefore, may disclose it as required to other clinical investigators and to 
Regulatory Authorities. 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) is completed.  
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 TMG.    
The results may be published or presented by the investigator(s), but the Funder 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. 
A Clinical Study Report summarising the study results will be prepared and submitted to the 
REC.  
 
 
 

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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: PROState Pathway Embedded Comparative Trial  
 
 
 
Protocol Number:  
19CX5601 
 
Signed:  
___________________________________________ 
 
 
 
 
 
Professor Hashim U Ahmed 
 
 
 
 
 
 
 
 
 
Date:  
 
_____________________ 
 
 
 
 
 
 

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Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
PROSPECT Protocol version 6.0 05 April 2022  
 
 
 
 
 
 
Page 67 of 71 
 
SIGNATURE PAGE 2 (Sponsor) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
Study Title: PROState Pathway Embedded Comparative Trial  
 
Protocol Number:  
19CX5601 
 
 
Signed:  
___________________________________________ 
 
 
 
 
 
Name of Sponsor’s Representative 
 
 
 
 
Title 
 
 
 
 
Sponsor name 
 
 
 
 
 
Date:  
 
_____________________ 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
PROSPECT Protocol version 6.0 05 April 2022  
 
 
 
 
 
 
Page 68 of 71 
 
SIGNATURE PAGE 3 (Statistician) 
   
The signatures below constitute approval of this protocol by the signatory.  
 
Study Title: PROState Pathway Embedded Comparative Trial  
 
Protocol Number:  
19CX5601 
 
 
 
Signed:  
___________________________________________ 
 
 
 
 
 
Dr Francesca Fiorentino 
 
 
 
 
Imperial Clinical Trials Unit and Division of Surgery 
 
 
Date:  
 
_____________________ 
 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
PROSPECT Protocol version 6.0 05 April 2022  
 
 
 
 
 
 
Page 69 of 71 
 
SIGNATURE PAGE 4 (Principal Investigator) 
 
The signature of the below constitutes agreement of this protocol by the signatory and 
provides the necessary assurance that this study will be conducted at his/her investigational 
site according to all stipulations of the protocol including all statements regarding 
confidentiality. 
 
Study Title: PROState Pathway Embedded Comparative Trial  
 
Protocol Number:  
19CX5601 
 
Address of Institution:  ____________________________________________ 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
Signed:  
 
 
 
 
____________________________________________ 
 
Print Name and Title: ____________________________________________ 
 
Date:  
 
 
 
 
 
_____________________ 
 
  
 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
PROSPECT Protocol version 6.0 05 April 2022  
 
 
 
 
 
 
Page 70 of 71 
 
PROSPECT STUDY APPENDICES 
Appendix A – Overall CONSORT Flowcharts for PROSPECT cmRCT  
 
 
 

Short Title: 
IP3-PROSPECT 
Protocol No:  
 19CX5601  
Sponsor: 
Imperial College London 
Version: 6.0 
Date: 05 APR 22 
 
 
CONFIDENTIAL   
PROSPECT Protocol version 6.0 05 April 2022  
 
 
 
 
 
 
Page 71 of 71