A Single Blinded, IDEAL Stage 3, Multi-Centre, Randomised Controlled Trial to Assess NeuroSAFE Robotic Assisted Radical Prostatectomy (RARP) vs Standard Robotic Assisted Radical Prostatectomy (RARP) in Men With Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: University College, London

 
 
NeuroSAFE Protocol Version 7.0 dated 14 February 2023 
IRAS Reference Number 220262 
 
 
 
A single blinded, IDEAL stage 3, multi-centre, randomised controlled trial to assess 
NeuroSAFE Robotic assisted radical prostatectomy (RARP) vs standard Robotic 
assisted radical prostatectomy (RARP) in men with prostate cancer 
 
Acronym: NeuroSAFE PROOF  
 
Chief Investigator 
Professor Greg L. Shaw 
Consultant Urologist (UCLH) and Professor of Urology (UCL) 
 
Supported by: 
NIHR Research for Patient Benefit (PB-PG-1216-20013) 
The Jon Moulton Charity Trust 
St. Peters Trust 
 
Sponsored by 
University College London (UCL) 
 
Protocol version number and date 
7.0 dated 14 February 2023 
 
Sponsor reference number: 
17/0443 
 
Clinicaltrial.gov reference number: 
NCT03317990 
 
 

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DECLARATIONS 
 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the investigator agrees to conduct the trial in compliance with the approved protocol and will 
adhere to the Research Governance Framework 2005 (as amended thereafter), the Trust Data 
& Information policy, Sponsor and other relevant SOPs and applicable Trust policies and legal 
frameworks. 
I (investigator) agree to ensure that the confidential information contained in this document 
will not be used for any other purposes other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
I (investigator) also confirm that an honest accurate and transparent account of the trial will 
be given; and that any deviations from the trial as planned in this protocol will be explained 
and reported accordingly. 
 
Chief Investigator: Greg Shaw 
Signature:    
Date: 14 Feb. 23 
Print Name (in full): Gregory L Shaw 
Position: Consultant Urologist (UCLH) and Professor of Urology (UCL) 
 
On behalf of the Trial Sponsor: PUSHPSEN JOSHI 
Signature:   
 
Date: 28/02/2023 
Position: RMG& MANAGER- UCLH &UCL JRO 
 
 
 
 
 

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TRIAL SUMMARY 
 
Title  
 
A single blinded, IDEAL stage 3, multi-centre, 
randomised controlled trial to assess 
NeuroSAFE Robotic assisted radical 
prostatectomy (RARP) vs standard Robotic 
assisted radical prostatectomy (RARP) in men 
with prostate cancer 
 
Version and Date  
7.0 dated 14 February 2023 
Chief Investigator 
 
 
Professor Greg L. Shaw 
Consultant Urologist (UCLH) and Professor of 
Urology (UCL) 
Euston Road, London 
E : gregshaw@nhs.net 
 
Co-Investigators 
Urology  
Professor John Kelly 
Professor of Uro-Oncology 
Research Department of General Surgery 
Division of Surgery & Interventional Sciences 
University College London 
E: j.d.kelly@ucl.ac.uk 
 
Mr Neil Oakley 
Consultant Urological Surgeon 
Royal Hallamshire Hospital, Sheffield 
Teaching Hospitals NHS Foundation Trust 
E: Neil.Oakley@sth.nhs.uk 
 
Professor Raj Persad 
Consultant Urological Surgeon 
Southmead Hospital, North Bristol NHS Trust 
E: Raj.Persad@nbt.nhs.uk 
 
Mr Jon Aning 
Consultant Urological Surgeon 
Southmead Hospital, North Bristol NHS Trust 
E: jonathan.aning@nbt.nhs.uk 
 
Mr Imran Ahmad 
Consultant Urological Surgeon 
Queen Elizabeth University Hospital, NHS 
Greater Glasgow and Clyde 

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E: imran.ahmad@glasgow.ac.uk 
 
 
Dr Lorenzo Dutto 
Consultant Urological Surgeon 
Queen Elizabeth University Hospital, NHS 
Greater Glasgow and Clyde 
E: Lorenzo.Dutto@ggc.scot.nhs.uk 
 
Dr Nicola Santoni 
Associate PI 
Queen Elizabeth University Hospital, NHS 
Greater Glasgow and Clyde 
E: Nicola.Santoni@ggc.scot.nhs.uk 
 
Mr Thomas Walton 
Consultant Urologist 
Nottingham University Hospitals NHS Trust 
E: thomas.walton@nuh.nhs.uk 
 
Co-Investigator 
Histopathology 
 
Dr Alex Freeman 
Consultant Histopathologist 
UCLH NHS Foundation Trust 
E: alex.freeman@nhs.net 
 
Dr Aiman Haider 
Consultant Histopathologist 
UCLH NHS Foundation Trust 
E: aiman.haider@nhs.net 
Co-Investigator 
Statistics 
 
Professor Sue Mallett 
Senior statistician 
Centre for Medical Imaging (CMI), UCL 
E: sue.mallett@ucl.ac.uk 
Co-Investigator  
Health Economics 
Dr Elena Pizzo,  
Senior Health Economist, Department of 
Applied Health Research, University College 
London 
E: e.pizzo@ucl.ac.uk 
Participant Identification centre 
(PIC) site investigator 
Mr Greg Shaw 
Bart’s Health NHS Trust 
Consultant Urological Surgeon 
E: gregshaw@nhs.net 
 
Dr Lorenzo Dutto 
NHS Greater Glasgow and Clyde 
Consultant Urological Surgeon 

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E: Lorenzo.Dutto@ggc.scot.nhs.uk 
 
Mr Anand Kelkar 
Barking, Havering and Redbridge University 
Hospitals NHS Trust 
Consultant Urological Surgeon 
E: anand.kelkar@nhs.net 
 
Trial management 
NCITA Clinical Trials Unit 
ncita.neurosafe@ucl.ac.uk 
 
Clinical Fellow 
Dr Ricardo Almeida Magana 
NeuroSAFE clinical fellow UCLH 
UCL Division of Surgery & Interventional 
Science 
E: r.magana@ucl.ac.uk 
 
Trial Manager 
Mr Nick Roberts 
NeuroSAFE Trial manager 
E: ncita.neurosafe@ucl.ac.uk 
Sponsor 
representative 
 
Pushpsen Joshi 
Joint Research Office, 
250 Euston Road 
4th Floor 
London 
NW1 2PG  
 E: randd@uclh.net.uk 
 
 
 
 

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Protocol Version History  
 
Version 
Number  
Date  
Protocol Update Finalised By 
(insert name of person):  
Reasons for 
Update  
1.0 
20 Oct 2017 
Chris Brew-Graves 
N/A 
2.0 
06 Feb 2018 
Jack Grierson 
Single centre 
trial amended 
to multi-centre 
3.0 
03 Sept 2018 Jack Grierson 
Feasibility 
phase 
amended to 
pilot phase 
4.0 
29 Aug 2019 
Jack Grierson 
Pilot phase 
amended to 
fully powered 
RCT 
5.0 
21 April 
2021 
Jack Grierson 
Research team 
changes, 
COVID 
mitigation 
strategies, trial 
methodology 
changes & 
change of CTU 
6.0 
03 August 
2022 
Nick Roberts 
Research team 
changes, 
update of BCR 
definition, IIEF 
source 
clarification, 
addition of 
details on 
analysis of 
patients with 
measurable 
persistent PSA 
after surgery, 
addition of 
EPIC-26 
questionnaire 
6.1 
07 
September 
2022 
Nick Roberts 
Update of BCR 
definition 
made in 
Version 6.0, 
redaction of 

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control arm 
baseline 
proportion % 
described in 
statistics 
section 
7.0 
14 February 
2023 
Nick Roberts 
Addition of 
patient long 
term follow up 
beyond 5 years 
(Visit 8). 
Funding 
duration 
extension. 
 
 

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Contents 
 
DECLARATIONS ......................................................................................................... 2 
TRIAL SUMMARY ...................................................................................................... 3 
Protocol Version History ............................................................................................... 6 
1 
ABBREVIATIONS AND GLOSSARY .............................................................. 11 
2 
TRIAL OVERVIEW ............................................................................................ 14 
3 
LAY SUMMARY ................................................................................................ 18 
 
Why is this research needed? ........................................................................ 18 
4 
BACKGROUND .................................................................................................. 21 
 
Prostate Cancer .............................................................................................. 21 
 
Radical prostatectomy and nerve sparing ...................................................... 21 
 
Robot-assisted radical prostatectomy (RARP) .............................................. 21 
 
Quality of life versus oncological outcome ................................................... 22 
 
Frozen section technique (NeuroSAFE). ...................................................... 23 
5 
HYPOTHESES & OBJECTIVES ........................................................................ 25 
 
Hypotheses .................................................................................................... 25 
6 
Objectives ............................................................................................................. 25 
 
Primary .......................................................................................................... 25 
 
Secondary ...................................................................................................... 25 
7 
TRIAL DESIGN ................................................................................................... 26 
 
Type of Trial .................................................................................................. 26 
 
Outcome endpoints ........................................................................................ 26 
7.2.1 
Primary ................................................................................................... 26 
7.2.2 
Secondary Endpoints ............................................................................. 27 
 
Trial Schedule ............................................................................................... 30 
 
Table of Assessments .................................................................................... 31 
8 
TRIAL ELIGIBILITY .......................................................................................... 32 
 
Number of sites ............................................................................................. 32 
 
Inclusion criteria ............................................................................................ 32 
 
Exclusion criteria ........................................................................................... 32 
 
Withdrawal criteria ........................................................................................ 32 
9 
SUBJECT RECRUITMENT ................................................................................ 33 
 
Identification of trial participant ................................................................... 33 
 
Screening and Consent .................................................................................. 33 
 
Alternative consenting procedures due to COVID-19 .................................. 34 

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9.3.1 
e-consent ................................................................................................ 34 
10 TRIAL INTERVENTIONS .................................................................................. 35 
 
Robot-assisted radical prostatectomy (RARP) .......................................... 35 
10.1.1 Control Arm: Standard RARP ............................................................... 35 
10.1.2 Intervention Arm: NeuroSAFE RARP .................................................. 35 
 
Multiparametric MRI prostate ................................................................... 37 
 
Other prostate evaluation technologies and co-enrolment ........................ 38 
 
UCLH Biobanking ..................................................................................... 38 
11 DATA COLLECTION ......................................................................................... 40 
 
Data transfer (handling, processing and storage) ...................................... 40 
 
Video Collection ........................................................................................ 41 
 
Health Economics Analysis ....................................................................... 41 
 
Electronic Patient Reported Outcome Measures (e-PROMs) ................... 41 
12 STATISTICS ........................................................................................................ 43 
 
Sample size ................................................................................................ 43 
 
Statistical Analysis .................................................................................... 45 
12.2.1 Intent to treat population ........................................................................ 45 
12.2.2 Per protocol population .......................................................................... 45 
12.2.3 Safety population ................................................................................... 45 
12.2.4 Statistical methods ................................................................................. 45 
12.2.5 Handling missing data ............................................................................ 46 
13 DATA MONITORING ........................................................................................ 47 
 
Discontinuation of the trial ........................................................................ 47 
13.1.1 Trial Discontinuation by the Sponsor .................................................... 47 
13.1.2 Discontinuation of Trial for an Individual Patient ................................. 47 
 
Quality assurance ....................................................................................... 48 
 
Assessment of safety ................................................................................. 48 
 
SAE Reporting ........................................................................................... 50 
 
Reporting Requirements ............................................................................ 50 
 
Flow of SAE Reporting ............................................................................. 51 
 
Expected Adverse Events .......................................................................... 52 
13.7.1 Notification of Death ............................................................................. 52 
13.7.2 Period of observation ............................................................................. 52 
14 ETHICAL CONSIDERATIONS ......................................................................... 53 
15 FINANCING AND INSURANCE ....................................................................... 54 
16 REPORTING AND DISSEMINATION .............................................................. 55 

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Patient and Public Involvement ................................................................. 55 
 
NeuroSAFE PhD report ............................................................................. 55 
17 REFERENCES ..................................................................................................... 57 
18 ROLES AND RESPONSIBILITIES .................................................................... 60 
 
 
 

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1 ABBREVIATIONS AND GLOSSARY 
 
Abbreviation 
or Term 
Definition/Explanation 
AE 
Adverse Event 
ADT 
Androgen Deprivation Therapy 
APR 
Annual Progress Report 
BCR 
Biochemical Recurrence 
C 
Celsius 
CLIA 
Clinical Laboratory Improvement Amendments 
CFR 
Code of Federal Regulations 
CMI 
Centre for Medical Imaging 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
CT 
Computed Tomography 
CTA 
Clinical Trial Application 
CTU 
Clinical Trials Unit 
CVs 
Curricula Vitae 
DCE 
Dynamic Contrast Enhanced 
DRE 
Digital Rectal examination 
DSUR 
Development Safety Update Report 
DWI 
Diffusion Weighted Imaging 
EC 
Ethics Committee 
EF 
Erectile Function 
EQ-5D 
EuroQol Group Patient Questionnaire 
ERSPC 
European Randomised Study of Screening for Prostate Cancer 
ET 
Early Termination 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GP 
General Practitioner 
HIFU 
High Intensity Focused Ultrasound 
HRQoL 
Health-Related Quality of Life 
H&E 
Haematoxylin & Eosin 
IB 
Investigator’s Brochure 
ICER 
Incremental Cost-Effectiveness Ratio 
ICF 
Informed Consent Form 
ICIQ 
International Consultation on Incontinence Questionnaire 
IFS 
Intra-operative Frozen Section 
IIEF 
International Index of Erectile Function 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LUTS 
Lower Urinary Tract Symptoms 
LPF 
Lateral Pelvic Fascia 
MCCL 
Maximum Cancer Core Length 

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MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
µg 
Microgram 
µm 
Micrometer 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mL 
Milliliter 
mm 
Millimeter 
MDT 
Multi-Disciplinary Team 
mpMRI 
Multi-parametric Magnetic Resonance Imaging 
MRI 
Magnetic Resonance Imaging 
N or n 
Number 
NCITA 
National Cancer Imaging Translational Accelerator 
NHS 
National Health Service 
NICE 
National Institute for Health and Clinical Excellence 
NIHR 
National Institute of Healthcare Research 
NNT 
Number Needed To Treat 
NS 
Nerve-sparing (technical part of RARP or RP) 
NOAEL 
No Observed Adverse Effects Level 
OAB 
Overactive Bladder 
OCT 
Optimal cutting temperature compound 
PDE5i 
Phosphodiesterase Type 5 Inhibitor 
PET 
Positron Emission Tomography 
pH 
Hydrogen Ion Concentration 
pT 
Pathological Tumour stage prostate cancer according to TNM 
PIS 
Participant Information Sheet 
PRN 
Pro re nata (taken as needed) 
PROM 
Patient Reported Outcome Measure 
PSA 
Prostate-Specific Antigen 
PSM 
Positive Surgical Margin 
PSS 
Prescribed Specialised Services 
PV 
Prostate Volume 
QoL 
Quality of Life 
RARP 
Robotic assisted radical prostatectomy 
RP 
Radical Prostatectomy 
RCT 
Randomised Control Trial 
REB 
Research Ethics Board 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 

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SITU 
Surgical & Interventional Trials Unit 
SOPs 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TCCL 
Total Cancer Core Length 
TRUS 
Transrectal Ultrasound 
UCL 
University College London 
UCLH 
University of London College Hospitals 
UK 
United Kingdom 
US 
United States 
WHO 
World Health Organization 
Wk 
Week 
w/v 
Weight Volume Ratio 
3D 
Three-Dimensional 
 
 
 
 

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2 TRIAL OVERVIEW 
 
Trial Title 
A single blinded, IDEAL stage 3, multi-centre, randomised 
controlled trial to assess NeuroSAFE Robotic assisted 
radical prostatectomy (RARP) vs standard RARPs in men 
with prostate cancer 
Short Title 
NeuroSAFE at prostatectomy to optimise oncological and 
functional outcome.  (NeuroSAFE PROOF)  
Aim 
This is an RCT to assess the differences in functional and 
oncological outcomes between RARP using the 
NeuroSAFE intraoperative frozen section technique to 
navigate safe nerve sparing and standard UK practice 
RARPs 
Inclusion criteria 
 
1. Men opting to undergo RARP for organ confined 
prostate cancer (including radiological t3a). 
2. Potent men (IIEF score of 22-25 without any erectile 
function medical assistance)(from baseline PROM or 
clinical notes) 
3. Men who are continent of urine (no self-reported 
urinary incontinence) 
4. Has given written informed consent 
5. Ability to read English sufficiently to answer 
questionnaires and understand PIS  
Exclusion criteria 
1. Unable to undergo RARP 
2. Known overactive bladder  
3. Any previous treatment for prostate cancer  
4. Previous/current hormone treatment for prostate 
cancer 
5. Nerve sparing deemed futile due to locally advanced 
disease by surgeon and radiologist 
Withdrawal criteria 
1. Unable to perform nerve sparing RARP as planned 
due to anatomical/technical difficulty during 
surgery 
2. Withdrawn consent 
Trial procedures 
Control arm - standard RARP:  
Nerve-sparing strategy during RARP guided by routinely 
available pre-operative and intra-operative 
patient/disease information; mpMRI, biopsy tumour 
histology, DRE. 
 
Intervention arm – NeuroSAFE RARP: 
Nerve-sparing strategy during RARP guided by routinely 
available pre-operative and intra-operative 
patient/disease information; mpMRI, biopsy tumour 

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histology, DRE and the NeuroSAFE technique during 
RARP. 
 
Outcomes and 
Analysis 
Primary outcome: 
 
• Comparison of the proportion of men who 
recover erectile function at 12-months according 
to allocated treatment arm (i.e. NeuroSAFE RARP 
[intervention] vs. standard RARP [control]). 
Erectile function is measured using the IIEF-5 
questionnaire, where recovered function is 
defined as a score of 21 or more.  
 
o Pre-defined sub-group analysis: 
comparison of the proportion of men who 
recover erectile function at 12-months 
according to treatment arm, restricted to 
men who did not receive a pre-operative 
radiologist recommendation for bilateral 
nerve sparing. 
 
For further sub-group analyses and sensitivity analyses, 
please see body of protocol, Outcomes Section. 
 
Secondary outcomes: 
 
There are 6 secondary outcomes: 
 
1) Urinary Continence 
 
• Comparison of the proportion of men who are 
continent at 3 months, measured using the ICIQ 
questionnaire, where continence is defined as a 
score of 5 or less between intervention and 
control arms.   
o Additional subgroup analysis: restricted to 
men who did not receive a pre-operative 
radiologist recommendation for bilateral 
nerve sparing. 
 
For further sub-group analyses and sensitivity analyses 
please see body of protocol, Outcomes Section. 
 
2) Biochemical Recurrence (BCR) 
 

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Comparison of the proportion of men with BCR between 
NeuroSAFE and control arms within 12 months of 
surgery.  BCR will be considered to have occurred when 
the post operative PSA measures >0.2ng/mL, or where 
the PSA level is less than 0.2 ng/mL but the trajectory 
suggests inevitable rise above 0.2 ng/mL according to the 
clinician looking after the patient. If PSA fails to nadir 
after surgery, this will not be considered BCR as this is 
probably related to micro metastatic disease not 
detected by preoperative imaging. 
For further descriptive analyses, sub-group analyses, and 
sensitivity analyses please see body of protocol, 
Outcomes Section. 
 
3) Additional oncological treatments 
 
• ‘Adjuvant treatment’ refers to men who undergo 
additional cancer treatment without having BCR.  
A descriptive analysis of the proportion of men 
undergoing adjuvant oncological treatments (ADT 
and/or radiotherapy and/or chemotherapy) at or 
before 12 months of surgery will be conducted. 
 
• ‘Salvage treatment’ refers to men who undergo 
additional cancer treatment following BCR. A 
descriptive analysis of the proportion of men 
undergoing adjuvant oncological treatments (ADT 
and/or radiotherapy and/or chemotherapy) at or 
before 12 months of surgery will be conducted. 
 
4) Quality of Life  
 
• A comparison of the proportion of men achieving 
the best quality of life according to the EQ-5D-5L 
between intervention and control arms. 
• Analysis of EQ-5D-5L scores to produce QALYs at 
12 months by arm 
• Analysis of RAND36 scores to produce QALYs at 
12 months by arm 
• Analysis of EPIC-26 scores at 36, 48 and 60 
months after surgery and a maximum frequency 
of annually thereafter 
 
5) Positive Surgical Margins (PSM) 
 

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• Descriptive tabulation of PSM rates between 
NeuroSAFE RARP and standard RARP arms.  PSMs 
will be grouped as:  
 
0. Negative margin 
1. Intraprostatic margins 
2. Non-intraprostatic margins ≤ 1mm (included) 
3. Large non-intra prostatic margins and >1mm 
4. Very large non-intraprostatic margins and >3mm 
and/or multifocal 
 
o Additional subgroup analysis: restricted to 
men who did not receive a pre-operative 
radiologist recommendation for bilateral 
nerve sparing. 
 
6) Health Economic Analysis 
 
• Use of the Health Economics Questionnaires to 
inform a health cost analysis of NeuroSAFE RARP 
vs. standard RARP. 
o Economic analysis to assess healthcare 
resources use by arm and cost analysis to 
assess:  
o Cost of intervention and control 
o Cost of NHS resource use (medications, 
physiotherapy,  
o Cost of private health care resources 
(medication, physiotherapy)  
o Other private/societal costs (productivity 
losses, caregivers costs, out of pocket cost 
for transport, equipment)  
 
For further sub-group analyses and sensitivity analyses 
please see body of protocol, Outcomes Section. 
 
Funding Duration 
This trial is funded until 30th November 2023 
Ethics 
All subjects must give signed informed consent. Subjects’ 
data will be handled according to regulatory 
requirements and be protected according to the EU 
Directive 2016/679 on data protection as well as local 
data protection requirements. UK Research Governance 
guidelines will be adhered to. The protocol must be 
approved by an independent Ethics Committee before 
use. 
 
 

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3 LAY SUMMARY 
 
 Why is this research needed? 
 
Prostate cancer is very common and results in the death of many men in the 
developed world. Prostate cancer that has not spread outside the prostate can 
usually be cured by surgical removal of the prostate gland (radical prostatectomy). 
Radical Prostatectomy can be associated with urinary incontinence due to damage to 
the involuntary sphincter and erectile dysfunction due to damage of the nerves that 
run within the outer coverings of the prostate. Surgical sparing of these nerves to 
preserve quality of life may risk leaving cancer cells behind often meaning that the 
patients need extra treatment with radiotherapy. This trial is designed to evaluate a 
new method designed to decrease the risk of compromising cancer control 
associated with sparing of the nerves as well as evaluate effects on the need for 
radiotherapy after surgery if cancer is left behind. We will also evaluate effects on 
the quality of life in patients who have undergone RARP. The trial is needed now 
because the nature of prostate cancers treated surgically is changing rapidly. The 
techniques developed in low-risk cancer to spare the nerves which run alongside the 
prostate, may not necessarily be safe when used on the more aggressive cancers we 
operate on nowadays and if they are adopted without adequate investigation, the 
risk is that patients will be exposed to increased risk of cancer recurrence and 
needing extra treatment with radiotherapy with consequent side effects and extra 
cost to the NHS. 
 
On the outside of the prostate, within its outermost coverings, run the nerves 
thought to be responsible for producing erections. Preservation of these nerves has 
also been linked to more rapid reestablishment of urinary continence following 
surgical removal of the prostate. Robotic technology has been developed which 
allows the prostate to be removed through very small incisions. The surgeon’s view 
is magnified in 3D, which facilitates the peeling off of the outer layers, containing the 
nerves (so called nerve sparing). With nerve sparing the nerves controlling erections 
are left intact whilst the prostate itself, along with the cancer within it, is removed. 
This increases the patient’s chances of getting erections of sufficient quality for 
penetrative sex.  Data from several case series, including our own, suggest that the 
higher the degree of nerve sparing performed, the more likely a patient is to be 
potent and continent of urine.  In our series, bilateral nerve sparing results in 85% of 
men being able to get usable erections*, whereas only 45% of men will have usable 
erections1* when only one side is spared. 
 
Nerve sparing has largely been developed and the effects have been evaluated in the 
USA where prostate cancer is detected at an earlier stage because PSA screening is 
performed commonly. In the UK, where PSA screening is not commonly carried out, 
tumours resected at surgery are larger and more aggressive, often having spread 
 
* At 2 years following surgery using Viagra or an equivalent PDE5i.  

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through the capsule of the prostate.  In addition, the move away from surgery for 
small low-grade tumours in the UK means that the prostate cancers treated by 
surgery are larger and more aggressive overall. This means that the tumours are 
closer to the outer limit of the prostate because the more aggressive tumours tend 
to work their way out through the outer capsule of the prostate. A nerve sparing 
approach is associated with an increased risk that tumour will be left on the surface 
of the resected specimen. This is referred to as a positive surgical margin (PSM). One 
of the principles of (radical) cancer surgery is that cancerous tissue should be 
removed with a covering of non-cancerous tissue to give the best chance of cure (a 
so called negative or clear surgical margin). Positive surgical margins are associated 
with an increased chance of recurrence following surgery and require further 
treatment, usually with radiotherapy, which is expensive and engenders its own side 
effects. 
 
We plan to evaluate the use of a modified version of a frozen section technique 
called NeuroSAFE (1) in promoting nerve sparing without diminishing the oncological 
effects of surgery by generating PSMs.  
 
During this frozen section technique, once the prostate is removed, the areas of 
prostate adjacent to the spared nerves are sliced from the surgical specimen and 
rapidly frozen and stained so that they can be examined carefully by a pathologist. If 
the pathologist identifies a positive surgical margin, the spared nervous tissue on 
that side will be surgically resected before the patient is woken up at the end of the 
operation. When this is done the cancer behaves as if it had been resected with a 
negative surgical margin at the outset. 
 
Frozen section analysis does not add much time to the surgical procedure, as once 
the prostate is removed, the rest of the operation (joining the bladder to the urethra 
and removing pelvic lymph nodes) can proceed whilst the frozen section analysis is 
performed. Patients enrolled to the trial will be randomised between A) standard UK 
nerve sparing practice, wherein the degree to which the nerves can be spared is 
determined by the operating surgeon based on clinical examination, biopsy results 
and multi-parametric MRI and B) bilateral nerve sparing with frozen section analysis.  
 
We recently surveyed UK robotic prostatectomists and confirm that currently UK 
surgeons predominately rely on MRI, biopsy and Digital Rectal Exam (DRE) findings 
to determine whether they can spare nerves, but that there is little consistency in 
the means by which a surgeon decides whether or not they can spare nerves in a 
particular case. Our survey tells us that UK surgeons do not use frozen section to 
direct nerve sparing with only 5% of UK prostatectomists ever having used it at all. 
 
What are the potential outcomes of this research? 
This trial will provide a thorough evaluation of a new technique designed to minimise 
the occurrence of PSM and exposure to extra treatment or cancer recurrence. It will 
generate vital data regarding the cost/benefit of using this procedure.  The 
relationship between the degree and frequency of nerve sparing on quality of life 

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will be evaluated in terms of sexual potency and urinary continence in UK patients 
undergoing RARP. The assessment of these functions will include patient reported 
outcomes. 
 
In summary this trial will test whether this new surgical technique can be used to 
make surgery safer and more effective whilst allowing improved quality of life for 
patients having surgery for prostate cancer. If the technique is proven effective, we 
will use the experience gained to promote its use throughout the NHS through 
training courses and publication and dissemination of the resultant data. Staff from 
centres participating in this trial will be fully trained in the NeuroSAFE technique. 
 
A patient and public involvement afternoon was held for participants of the 
NeuroSAFE PROOF feasibility trial, family members, men with prostate cancer, and 
staff members at UCLH.  The event was supported by the charity Orchid Cancer 
appeal.  The high levels of attendance were demonstrative of the support within our 
patient group for the work of this trial.  We listened to the comments made by 
participants and members of the public and have made some changes to the design 
of our trial as a result of this feedback. 
 
 

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4 BACKGROUND 
 
 Prostate Cancer 
 
Prostate cancer is now the most common cancer in men in the UK. More than 41,700 
men were diagnosed in the UK in 2011 with areas of London identified as having 
some of the highest incidence rates nationally. While survival has increased 
substantially over the last 40 years, prostate cancer is the second highest cause of 
male cancer death in the UK (2). The incidence of prostate cancer in Northeast 
London (142.8 per 100,000) is higher than the national average (105.8 per 100,000). 
Consequently, prostate cancer is the most commonly diagnosed cancer across 
Northeast London with the number of men living with and after prostate cancer in 
the UK predicted to rise. (3) Despite being very effective at curing localised prostate 
cancer, RARP is associated with distressing physical and psychological symptoms, 
including urinary incontinence and erectile dysfunction, which can affect individuals 
for many years. (4) Following radical prostatectomy 5% of men have long term 
urinary incontinence and need to wear pads or consider further surgical treatment 
to stop the leakage. 95% of men who undergo non-nerve sparing radical 
prostatectomy suffer erectile dysfunction, which is resistant to treatment with drugs 
like Viagra, even after a period of 2 years following surgery. 
 
Treating cancer and dealing with the side effects of treatment is expensive. The 
modern NHS is challenged with needing to develop and evaluate the effectiveness of 
new treatments whilst minimising treatment toxicity.(5) 
 
 Radical prostatectomy and nerve sparing 
 
The first radical retropubic prostatectomy was performed by Millen in 1947. In the 
1980s Walsh and co-workers identified the parasympathetic nerves derived from the 
pelvic plexus as they pass across the tips of the seminal vesicles and then along the 
posterolateral aspect of the prostate, between the true capsule and the lateral 
prostatic fascia, to the corpora cavernosae. Stimulation of these nerves brings about 
penile erection. (6) The function of these nerves has also been linked to urinary 
continence. (7) 
 
 Robot-assisted radical prostatectomy (RARP) 
 
The 1990s saw the advent of minimally invasive radical prostatectomy using 
manually controlled laparoscopic equipment. (8) Advancing robotic technology 
means that nowadays, surgical removal of the prostate using a robotic system is 
possible with the first RARP performed in 2000. (9) Since then, RARP has become the 
gold standard in prostate cancer surgery to such an extent that in 2008 80% of 
radical prostatectomies performed in the USA were done robotically. The National 
Prostate Cancer Audit report 2020 shows that 89% of UK radical prostatectomy is 
now performed by RARP(10). RARP is associated with a lower operative blood loss, 

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blood transfusion rate than laparoscopic surgery and a shorter hospital stay than 
open surgery. RARP results in oncological outcomes which are at least non-inferior to 
open or laparoscopic surgery.(11) (12) 
 
A recent investigation, on behalf of the NIHR Health Technology Assessment, of the 
cost effectiveness of robotic radical prostatectomy (without frozen section analysis) 
concluded that avoidance of the need for adjuvant treatment by prevention of 
positive surgical margins contributed significantly to the cost effectiveness of robotic 
prostate surgery. (13) An economic means by which to decrease the rate of PSMs 
further has the potential to make RARP more cost effective still. 
 
 Quality of life versus oncological outcome 
 
The majority of localised prostate cancer can be cured by surgery, with 10 year 
prostate cancer specific survival reported at 92% (14). Radical prostatectomy has 
been shown to be more effective than watchful waiting (15) and radical radiotherapy 
for treating significant prostate cancer (16). RARP is a significant physiological 
challenge for the patient. Since alternative treatment with radiotherapy is available, 
men with medical comorbidities usually opt to have radiotherapy. Younger, fitter 
men tend to have surgery. (16) These men are more commonly potent and sexually 
active as well as continent of urine compared with their older, less well counterparts. 
Thus, these are the men who have most to lose in terms of quality of life as well as a 
longer life expectancy over which to have to deal with any functional deficit.  
In order to try to limit the detrimental effects on Quality of Life (QoL), the 
neurovascular bundles can be carefully peeled off the sides of the prostate at 
surgery (17). In doing so, the prostate capsule is necessarily exposed, and less tissue 
intervenes between the prostate capsule and the edge of the resected specimen. 
Thus, the rate of PSM is increased. This is more likely with high volume or aggressive 
tumour, which is more likely to have breached the prostate capsule (pT3a) where 
any overlying connective tissue coverings (if present) will become the margin of the 
resected specimen. If pT3a disease is suspected the nerves cannot be spared without 
risking a positive surgical margin, often necessitating adjuvant radiotherapy. Pre-
operative MRI is not very good at distinguishing organ confined prostate cancer from 
that which has breached the prostatic capsule. (18) Radiotherapy compounds 
urinary incontinence and erectile dysfunction, as well as resulting in gastrointestinal 
toxicity and an, albeit low, risk of inducing secondary neoplasms.  
 
Current UK nerve sparing practice involves the operating surgeon deciding which 
nerves he feels he can spare based on the clinical examination, mp-MRI and biopsy 
findings. However, our ability to detect capsular breach by DRE, mp-MRI or from 
biopsy results is very limited. For example mp-MRI has been shown in a recent 
systematic review of 4001 patients to have a sensitivity of only 57% for detecting 
capsular extension. (18) Unsurprisingly, little consensus exists as to when a patient 
should have nerve sparing on a particular side or not for a given set of DRE/biopsy  
and MRI findings, as demonstrated with our recent survey of UK robotic surgeons 
who perform radical prostatectomy. A Delphi process to identify consensus around 

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nerve sparing amongst UK radical prostatectomists has been initiated by the 
research team. 
 
At UCLH where we perform approximately 800 RARPs per annum.  Of these, 
approximately 40-50% are performed for high-risk disease according to the EAU pre-
operative risk classification score.  Accordingly, relatively few (approximately 40% in 
2018) are afforded the potential functional recovery benefits of a bilateral nerve-
sparing RARP due to an excess perceived risk of leaving PSM and exposing patients 
to the need for subsequent adjuvant cancer therapies (ADT and radiotherapy) (data 
not published, available on request).  
 
Surgeons from the USA have developed the technique for nerve sparing. In an 
unscreened UK population, resected prostate cancer volume is greater than in a 
screened population like that of the USA. (20) Widespread adoption of nerve sparing 
has taken place in the USA despite a lack of level-one evidence. (21) Adoption of 
nerve sparing in the UK should be undertaken with care unless our patients are to be 
exposed to unjustifiable risk. 
 
Should a positive surgical margin occur, the patient is at significantly higher risk of 
treatment failure (biochemical recurrence) and a consequential need for salvage 
treatment compared to those in whom the surgical margins were clear. (22) (23)  
 
 Frozen section technique (NeuroSAFE). 
 
The NeuroSAFE technique was developed at the Martini Klinik in Germany. 
NeuroSAFE has been shown to increase the rate of nerve sparing and reduce the rate 
of PSM at RARP in observational studies. Currently, almost all patients treated with 
nerve sparing radical prostatectomy at the Martini Klinik undergo a NeuroSAFE 
procedure. However, the procedure is relatively costly as it is labour intensive and 
requires a consultant pathologist to examine the sections. (1) 
 
The technique itself does not result in a significant increase in operative time. This is 
because the specimen is extracted immediately when it is detached from the 
adjacent tissues and sent for frozen section analysis. Whilst this analysis is underway, 
the lymphadenectomy and fashioning of the urethro-vesical anastomosis can be 
performed. With this technique >99 % of pathologically organ-confined cancers and 
>90% of capsular-penetration (pT3a) or seminal vesicle (pT3b) invading tumours can 
be offered a nerve-sparing procedure, while reducing the rate of positive margins at 
the dorsolateral aspect to <1% and by more than 50% overall. If a posterolateral 
positive surgical margin is detected, resection of the NVB has been shown to result in 
oncological outcomes similar to if a negative surgical margin had been achieved in 
the first place. (24)  
 
A further modification of the NeuroSAFE system has been developed and piloted at 
the Lister Hospital in Stevenage by the collaborators on this project. The Lister 

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Hospital is currently the only UK centre offering frozen section analysis of the 
neurovascular bundles routinely, outside of this trial. 
 
A systematic review has been performed by our group on intra-operative frozen 
section (IFS) evaluation of the prostate margin during RP.  Medline, EMBASE and the 
Cochrane Library were systematically searched without time nor language 
limitations (CRD4201912594).  Ten non-randomized comparative studies (including 
16, 897 patients) were retrieved.  According to risk of bias assessment, seven studies 
suffer from serious risk of bias, whereas three studies suffer from moderate risk of 
bias.  Performance of IFS greatly differed technically between studies.  Eight studies 
report a reduction in rates of PSM (-1.4% to -14.5%) with the use of IFS and two 
studies report higher PSM rates (+0.4% to +10%) in IFS group.  Four studies that 
perform IFS systematically at the posterolateral margin of the prostate all report 
either improved NVB preservation or improved erectile function (EF) recovery.  Our 
groups’ conclusions included that, no RCTs were identified, and most included 
studies are at high risk of bias. Furthermore, only very few of the studies included 
results on either long term oncological or functional outcomes.  Within the 
limitations of this review, the evidence suggests that IFS during RP can modestly 
reduce PSM rates.  IFS performed systematically at the posterolateral margin of the 
prostate (the NeuroSAFE technique) can facilitate more NVB preservation, which 
may contribute to improved patient functional outcome recovery, though this has 
not been proven in prospective studies yet.  In short, randomized, prospective, 
standardized research with long term oncological and functional outcomes are 
lacking to date.  We feel this further strengthens the case for the conduct of the 
NeuroSAFE PROOF trial. 
 
 

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5 HYPOTHESES & OBJECTIVES 
 
 Hypotheses 
 
• Men undergoing NeuroSAFE RARP will experience superior EF recovery 
compared to men undergoing standard RARP. 
 
• Men undergoing NeuroSAFE RARP will experience improved recovery of 
urinary continence at 3 months following surgery compared to men 
undergoing standard RARP. 
 
• Men undergoing NeuroSAFE RARP will experience the same rates of cure 
from surgery compared to those undergoing standard RARP.   
 
6 Objectives 
 
 Primary  
 
To assess the difference in erectile function recovery between men undergoing 
standard RARP (control arm) and NeuroSAFE RARP (intervention arm) at 12 months 
following treatment using the IIEF-5 questionnaire.  
 
 Secondary 
 
1. To evaluate the differences in urinary continence recovery in the early period 
following treatment (3 and 6 months) between men undergoing standard 
RARP (control arm) and NeuroSAFE RARP (intervention arm). 
2. To evaluate the differences in oncological outcomes (including BCR and 
administration of adjuvant/salvage treatments) between men undergoing 
standard RARP vs. NeuroSAFE RARP at 12 months. Additional analysis is 
intended at 5 years post-surgery. 
3. To evaluate differences in overall quality of life outcomes between men 
undergoing standard RARP vs NeuroSAFE RARP at 12, 24, 36, 48 and 60 
months after surgery2 and a maximum frequency of annually thereafter. 
4. To evaluate differences in recovery of erections after 12-months and up to 2 
years between men undergoing standard RARP vs NeuroSAFE RARP  
5. Economic analysis to assess health resource use between standard RARP vs 
NeuroSAFE RARP at 12 months and up to 2 years post treatment. 
 
 
 
2 Evaluation after 12 months dependent on future funding 

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7 TRIAL DESIGN 
 
 Type of Trial 
 
A single blinded, IDEAL stage 3, multi-centre, randomised controlled trial to assess 
NeuroSAFE Robotic assisted radical prostatectomy (RARP) vs standard RARP in men 
with prostate cancer. Men will be randomised 1:1 to NeuroSAFE RARP (intervention 
arm) vs Standard RARP (control arm). This trial aligns with an IDEAL framework Stage 
3 Assessment for the evaluation of complex surgical interventions. 
 
 Outcome endpoints 
 
7.2.1 Primary 
 
Comparison of the proportion of men who recover erectile function at 12 months 
allocated to the NeuroSAFE intervention versus the control arm. Erectile function is 
measured using the IIEF-5 patient reported outcome questionnaire, where 
recovered function is defined as a score of 21 or more.  
 
Patient Answers to the IIEF-15 
 
• Patients should be made aware before filling in their follow-up visit 
questionnaire responses, that oral medications such as PDE5 inhibitors (e.g. 
sildenafil, tadalafil and others of the same class) will be permitted when 
taking into account the strength of erection achievable during intercourse or 
sexual stimulation.   
• For the purposes of answering the IIEF-15 questions, erections achieved with 
the assistance of ancillary erectile aids such as the vacuum pump, intra-
cavernosal injections, penile creams and prostheses should not be considered 
in the answers. The reason for this division is that the ancillary erectile aids 
(pumps, injections) are not related to cavernosal nerve preservation (NS 
RARP) and therefore the inclusion of these devices in the answers would 
introduce confounding. 
• Erectile function will also be assessed, including use of erectile function aids 
by the additional erectile function questionnaire CRF.  
 
Verbal questionnaire responses (telephone) 
 
• Since the Covid-19 Pandemic and government restrictions on movement 
including hospital appointments, the NeuroSAFE PROOF team have been 
conducting trial follow-up visits via telephone.  All trial questionnaires have 
been sent to participants in the post. In order maintain data completeness on 
key outcome measures (such as erectile function at 12-months [IIEF-15] and 
urinary continence at 3 months [ICIQ]), the trial clinical team have been 
administering these PROM questionnaires over the telephone. 

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• As of protocol version 5.0, to ensure data completeness and to avoid 
submitting repeated protocol deviations for each instance, this method of 
data capture is now an accepted method of data collection. Any paper copies 
returned by post will supersede verbal responses. 
• In order to distinguish between source data origins, a new electronic CRF 
database will have the facility to record whether PROM items were obtained 
by paper questionnaires submitted by post, electronic versions submitted 
following email reminders, or verbally with a clinician over the telephone. 
 
Further planned analyses: 
 
• Additional subgroup analysis: restricted to men who did not receive a pre-
operative radiologist recommendation for bilateral nerve sparing. 
• Additional subgroup analysis: patients who did not receive adjuvant 
treatment (adjuvant therapy defined as any additional treatment without a 
PSA>0.2 ng/ml). 
• Sensitivity analyses: additional analysis at 12 months  
o (a) IIEF-5 using a threshold >=15  
o (b) IIEF-5 using a threshold of >=2 for question 3 
• Descriptive analysis of IIEF-5 at 3-, 6-, 12- and 24-months post-surgery3 
 
 
 
7.2.2 Secondary Endpoints 
 
7.2.2.1. Urinary Continence 
 
Comparison of the proportion of men who are continent at 3 months, measured 
using the ICIQ PROM, where continence is defined as a score of 5 or less, between 
the NeuroSAFE RARP arm and the standard RARP arm. 
 
• Sensitivity analyses: Analysis of incontinence at 6 months ICIQ score of 5 or 
less 
• Additional subgroup analysis: restricted to men who did not receive a pre-
operation radiologist recommendation for bilateral nerve sparing. 
• Additional subgroup analysis: patients who did not receive adjuvant 
treatment (adjuvant therapy defined as any additional treatment without a 
PSA>0.2 ng/ml)  
• Descriptive analysis of ICIQ scores at 3-, 6-, 12- and 24-months post-surgery4 
 
 
 
 
 
3 Analysis after 12 months dependent on future funding 
4 Analysis after 12 months dependent on future funding 

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7.2.2.2.  BCR 
 
Comparison of the proportion of men with BCR between NeuroSAFE and control 
arms within 12 months of surgery.  BCR will be considered to have occurred when 
the post operative PSA measures >0.2 ng/mL, or where the PSA level is less than 0.2 
ng/mL but the trajectory suggests inevitable rise above 0.2 ng/mL according to the 
clinician looking after the patient. If PSA fails to nadir after surgery, this will not be 
considered BCR as this is probably related to micro metastatic disease not detected 
by preoperative imaging. Patients with demonstration of metastases on imaging will 
not be considered as BCR for the same reason. 
 
• Follow up time of 12 months is defined as cumulative time up to the 12-
month visit. Patients visits after more than 13.5 months post-surgery will not 
be included (12 months + 6 weeks max visit window).  
• Additional descriptive analysis will report recurrences across all patients at 
the following times: Within 3 months (+/- visit window) and within 6 months 
(+/- visit window). 
• Descriptive analysis of BCR for each arm according to  
o (a) Gleason grade  
o (b) TNM stage  
o (c) pre-operative PSA level  
o (d) routinely used risk classifiers (D’Amico, CAPRA, EAU) (e) time of 
recurrence. 
 
If patients have a low but detectable PSA level the frequency of testing would be 
increased from the usual schedule (3,6,9,12 months) depending on the trajectory 
and level of concern of the clinician looking after the patient. 
 
 
7.2.2.3.  Additional oncological treatments 
 
For men who receive additional cancer treatment, despite not having reached a PSA 
threshold of PSA>0.2 ng/ml post-surgery will be considered as having undergone 
‘adjuvant treatment.’  Descriptive analysis of proportions of men undergoing 
adjuvant oncological treatments at or before 12 months of surgery, including 
tabulating the types of treatment that these men underwent.  Reasons for adjuvant 
treatment (i.e. before BCR) will be documented where possible. 
 
Men who receive additional cancer treatment, following a PSA at or above the 
threshold of PSA>0.2 ng/ml post-surgery will be considered as having undergone 
‘salvage treatment.’  Descriptive analysis of proportions of men undergoing salvage 
oncological treatments at or before 12 months of surgery, including tabulating the 
types of salvage treatment that these men underwent. 
 

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7.2.2.4.  Quality of life 
 
Comparison of the proportion of men’s quality of life on NeuroSAFE intervention 
compared to control arm.  
• 
Analysis of EQ-5D-5L scores to produce QALYs at 12 months by arm 
• 
Analysis of RAND36 scores to produce QALYs at 12 months by arm 
• 
Analysis of EPIC-26 scores to produce QALYs at 36-, 48-, and 60 months and a 
maximum frequency of annually thereafter by arm 
 
Graphical presentation and descriptive analysis of RAND36 and EQ-5D-5L at 3-, 6-, 
12- and 24-months post-surgery.   
 
 
7.2.2.5.  Positive Surgical Margins (PSM) 
 
Descriptive tabulation of PSM rates between NeuroSAFE RARP and standard RARP 
arms.  PSM will be grouped as:  
 
0. Negative margin 
1. Intraprostatic margins 
2. Non-intraprostatic margins ≤ 1mm (included) 
3. Large non-intra prostatic margins and >1mm 
4. Very large non-intraprostatic margins and >3mm and/or multifocal 
 
Additional subgroup analysis: restricted to men who did not receive a pre-operative 
radiologist recommendation for bilateral nerve-sparing. 
 
7.2.2.6.  Health Economic Analysis 
 
Use of the Health Resource Questionnaires to inform a health cost analysis of 
NeuroSAFE RARP vs. standard RARP. Please see section 11.3. 
 
• Descriptive analysis by arm 
 
• Economic analysis to assess healthcare resources use by arm and cost 
analysis to assess:  
o Cost of intervention and control 
o Cost of NHS resource use (medications, physiotherapy 
o Cost of private health care resources (medication, physiotherapy) 
o Other private/societal costs (productivity losses, caregivers costs, out 
of pocket cost for transport, equipment)  
 
 

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 Trial Schedule 
 

 
 
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 Table of Assessments 
 
*P – Postal, E – Email, C – Clinic, T - telephone 
 
** after visit 8 data to be collected for a maximum frequency of annually  
 
5 Visits after 12 months dependent on future funding 
Visit 
Screening/
Baseline 
Randomisation 
Treatment 
Visit 1 
Visit 2 
3 
months 
(±6 
weeks) 
Visit 3 
6 
months 
(±6 
weeks) 
Visit 4 
12 
months 
(±6 
weeks) 
Visit 55 
2 years 
(±6 
weeks) 
Visit 6 
3 years 
(±6 
weeks) 
Visit 7 
4 years 
(±6 
weeks) 
Visit 8 
5 years 
(±6 
weeks) 
 
After 
Visit 
8** 
Informed consent   
x 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
Fitness for surgery assessment 
x 
 
 
 
 
 
 
 
 
 
 
PSA 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Standard care referral pathway to regional 
uro-oncology centre  
x 
 
 
 
 
 
 
 
 
 
 
MRI guided pre-op surgical planning 
 
 
x 
 
 
 
 
 
 
 
 
RARP (standard/control or 
NeuroSAFE/intervention) 
 
 
x 
 
 
 
 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
EQ-5D-5L – (P/C/E/T)* 
x 
 
 
x 
x 
x 
 
 
 
 
 
ICIQ – (P/C/E/T)* 
x 
 
 
x 
x 
x 
 
 
 
 
 
IIEF-5 – (P/C/E/T*) 
x 
 
 
x 
x 
x 
 
 
 
 
 
RAND36 – (P/C/E/T)* 
x 
 
 
x 
x 
x 
 
 
 
 
 
Additional Erectile Function (EF) 
questionnaire (P/C/E/T)* 
 
 
 
x 
x 
x 
 
 
 
 
 
Additional Treatments Assessment 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Health Resource Diaries data collection 
 
 
 
x 
x 
x 
x 
 
 
 
 
RAND36, IIEF, EQ-5D-5L, ICIQ and 
Additional EF questionnaire – (P/E/C/T) 
 
 
 
 
 
 
x 
 
 
 
 
EPIC-26 questionnaire (P/E)* 
 
 
 
 
 
 
 
x 
x 
x 
x 

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8 TRIAL ELIGIBILITY 
 
 Number of sites 
 
This trial will be run as a multi-centre, IDEAL stage III trial. There will be a 
combination of recruiting centres and participant identification centres (PIC sites). 
 
 
 Inclusion criteria 
 
1. Men opting to undergo RARP for organ confined prostate cancer 
(including radiological t3a). 
2. Potent men (IIEF score of 22-25 not using PDE5i or other medications 
or devices for first 5 questions at baseline (from baseline PROM or 
clinical notes) 
3. Men who are continent of urine (no self-reported urinary 
incontinence) 
4. Has given written informed consent 
5. Ability to read English sufficiently to answer questionnaires and 
understand PIS  
 
 Exclusion criteria 
 
1. Unable to undergo robotic prostatectomy 
2. Known overactive bladder  
3. Previous treatment for prostate cancer  
4. Previous/current hormone treatment for prostate cancer 
5. Nerve sparing deemed futile due to locally advanced disease by 
surgeon and radiologist  
 
 
 Withdrawal criteria 
 
1. Unable to perform nerve sparing as planned due to 
anatomical/technical difficulty during surgery. Intention to treat 
analysis will be undertaken 
2. Patient changes their mind 
 
 
 
 

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9 SUBJECT RECRUITMENT 
 
 Identification of trial participant 
 
Patients who potentially meet the eligibility criteria will be identified by the clinical 
team or during the regional urology cancer MDT team meetings at participating 
sites. They will be approached by one of the clinical team initially and then the trial 
team if they are willing to discuss the trial further. 
 
These potential trial patients will be given the ethics committee approved PIS in the 
form of a physical copy or by email. The patient must be given sufficient time for 
consideration (without breaching the NHS cancer treatment times) and given the 
opportunity to ask questions about the trial before deciding whether or not to 
participate. The right of the patient to refuse to participate in the trial, with or 
without giving a reason, must be respected.  If they are willing to participate in the 
trial, they will be asked for their informed consent to participate in this trial. PIC sites 
can issue a PIS only. 
 
 Screening and Consent 
 
After a potential participant has had sufficient time to read the PIS, the enrolment 
process will follow these steps: 
 
• The purpose of the research and the trial procedure is outlined again to the 
participant to ensure they understand. If the subject is willing to proceed, the 
participant will be asked to sign the approved trial consent form. This form 
may be a hard copy or an electronic consent form sent via an NHS account to 
the participants email. The original signed consent form will be filed in the 
investigator site file (ISF) after co-signature by an appropriate member of the 
research team. A copy will then be given to the participant and a copy filed in 
the hospital case notes. In the case of an electronic consent form, once 
signed and sent back to the research team, a fully co-signed copy is sent back 
to the participant, a copy is printed and stored in the ISF and a copy is stored 
in the hospital case notes. Please see section 9.3 for further details on e-
consent. 
• If the participant is willing to take part in the trial, eligibility to enter the trial 
is assessed based on inclusion and exclusion criteria. If all trial criteria are 
met, the screening visit CRF is completed. If a participant declines, this is also 
recorded in the screening log. A unique screening number will be assigned to 
participants recorded on the screening log.  
• The participant is deemed to be recruited into the trial and the participant’s 
GP is informed. At this point a unique subject trial number is allocated. 
• Using the Sealed Envelope randomisation system, the patient is randomised 
using their allocated trial number and will be assigned to either the control or 
intervention arm. They will then be informed of their date for surgery. 

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• The patient will be blinded as to which arm they are randomised to. The 
surgeon will not be blinded.  Unblinding will only be performed if an adverse 
event occurs where knowledge of allocation is perceived by the PI to be 
important in determining ongoing management. 
 
  Alternative consenting procedures due to COVID-19 
 
9.3.1 e-consent 
 
In line with the HRA COVID-19 guidance released on 28 May 2020, electronic 
methods for seeking, confirming and documenting informed consent in research 
studies can now be designed to  minimise patient contact and reduce risk to both 
patient and healthcare practitioner (https://www.hra.nhs.uk/covid-19-
research/seeking-consent-covid-19-research/). This has been implemented via an 
online consent form mimicking that of the currently approved paper copy.  
 
The e-consent form is built using the Research Data Collection Service (REDCap). 
Owing to the process collecting patient identifiable data the e-consent forms, resides 
within the REDCap service hosted behind the UCL Data Safe Haven which conforms 
to NHS Data Security & Protection Toolkit and ISO 27001 Information Security 
standards (https://www.ucl.ac.uk/isd/services/file-storage-sharing/data-safe-haven-
dsh). 
 
 
 

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10 TRIAL INTERVENTIONS 
 
 Robot-assisted radical prostatectomy (RARP) 
 
Patients will undergo RARP using the DaVinci surgical system as per standard of care 
in the NHS, and by a surgeon who has performed a minimum of 100 cases.  
 
10.1.1  Control Arm: Standard RARP 
 
Standard RARP (control arm) is performed as per NHS routine practice at 
participating regional uro-oncology sites.  Pre-operative parameters used to guide 
surgeon Nerve Spare (NS) decision include mpMRI NS planning sheet prepared in 
conjunction with a consultant genito-urinary radiologist, prostate biopsy tumour 
histology information and digital rectal examination under general anaesthesia.   
Individual surgeons are asked after RARP to grade the quality of NS performed on 
each side numerically as seen below (25): 
 
• Grade 0 - No nerve spare.  Wide excision of lateral pelvic fascia (LPF) and 
Denonvilliers’ fascia. 
• Grade 1 - Limited nerve spare, or partial/incremental nerve spare.  Incision 
through outer compartment of LPF. 
• Grade 2 – Interfascial nerve spare.  LPF is taken just outside the layer of the 
veins of the prostate capsule. Still largely preserving the large neural trunks 
(also known as the NVBs). 
• Grade 3 – Intrafascial nerve spare.  LPF is taken just outside the prostate 
capsule.  Represents greatest possible NS. 
 
NeuroSAFE PROOF collects detailed information on histological surgical margin 
status for safety and future publication purposes. Descriptions of histological 
diagnosis can differ between sites due to varying interpretations of histological 
analyses. In line with quality assurance, we will request anonymised pathology 
reports to ensure accurate, standardised reporting in the trial database. This will 
occur across both arms of the trial.   
 
10.1.2 Intervention Arm: NeuroSAFE RARP 
 
NeuroSAFE RARP (intervention arm) will be performed in accordance with previously 
described methods, initially developed at the Martini Clinik, Hamburg, Germany.  All 
patients in the NeuroSAFE arm will undergo initial bilateral NS where technically 
possible. The procedure differs from standard RARP in that initial insertion of the 
robotic camera port is through a modified incision using the Alexis Laparoscopic 
System (Applied Medical, Rancho Santa Margarita, CA).   
Once the specimen is disconnected from its attachments, the specimen can be 
removed from the patient through the protected incision immediately. 
Pneumoperitoneum can be re-established quickly by placing the laparoscopic cap 
back on the Alexis.  

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The specimen will then be painted by the operating surgeon (sites may differ, but at 
UCLH; yellow for left and green for right side of the prostate). The painted areas can 
be sprayed with a fixative spray if site prefers (to prevent ink running). The specimen 
will be delivered expediently to the pathology laboratory where frozen section 
analysis of the painted areas will be undertaken. Whilst this analysis is taking place 
the robot will be re‐docked and pneumoperitoneum established. The robotic 
instruments will be reinserted. The surgeon will proceed to fashion the urethra-
vesical anastomosis and perform a pelvic lymphadenectomy (where indicated) whilst 
the result of the frozen section analysis is awaited. 
Upon delivery of the prostate gland to the pathology lab, a sharp blade will be used 
to remove the pre-painted surface of the gland (which had been in contact with the 
neurovascular bundles). The tissue sample will be snap frozen and embedded 
in OCT. Using a cryostat, 10-micron thick slices will be placed on slides. The entire 
length of the area of interest will be sampled in this way generating an average of 
5 frozen sections per side and approximately 10 in total.  The slides will be stained 
with H&E and will be examined by a consultant pathologist. As soon as examination 
is complete the pathologist will telephone the operating surgeon to give the result. 
On frozen section analysis, presence of cancer cells at the inked surface margin of 
the specimen constitutes a positive margin and the length of any positive surgical 
margin will be recorded. 
Detailed results of the frozen section examination will be collected and included in 
the results, including number of sections positive, length of positive margin, grade of 
cancer cells seen at the margin, identity, and seniority of pathologist.  When the 
frozen section examination demonstrates cancer at the margin of the prostate as per 
pathology reporting protocol, secondary resection (SR) of the NVB is performed 
according to one of two ways on each side*: 
 
1. No tissue resected 
or 
2. Entire neurovascular bundle resected.   
 
*In the presence of an IFS PSM, the performance of SR of the ipsilateral NVB will be 
made if any of the following are present: 
 
(1) any PSM on multiple sections on a side, 
(2) any Gleason grade 4 or grade 5 adenocarcinoma at the margin. 
(3) any single section PSM >2 mm of Gleason Grade Group 1. 
 
If none of the above are present (including up to 2mm of Gleason Grade 3 at the 
inked margin) no SR will be performed. 
 
Technically during surgery, SR of the ipsilateral NVB is performed in the following 
way: all tissue from the cut edge of Denonvilliers’ fascia medially, the pararectal fat 
laterally, the pedicle cranially, and just beyond the urethrovesical anastomosis 
(including the puboprostatic ligament and Walsh’s pillar) caudally is removed en 

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bloc.  Secondarily resected tissue is sent for routine paraffin embedded histological 
analysis and is not analysed as part of the intraoperative frozen section.   
 
Detailed times of the beginning of the RARP, the removal of the prostate for 
specimen painting, arrival of specimen in laboratory, communication of details of 
fresh frozen section to the surgical team and finishing the RARP are recorded on the 
day of surgery. 
 
When recording a secondary resection in the database (if applicable), this will be 
recorded as either: 
 
• No tissue resected (due to none of the above 3 conditions being present) 
• Entire bundle resected (due to 1 or more of the above conditions being met) 
 
If the entire bundle is resected, this will automatically be considered as Grade 0, or 
non-nerve spare, on the side that SR was performed. 
 
 
 Multiparametric MRI prostate 
All patients will have pre-biopsy mpMRI as per the local practice’s diagnostic 
pathway.  All radiologists will have at least 2 years of experience in prostate MRI 
reading.  MRI diagnostic tumour detection performance is not formally assessed as 
all patients enrolling into NeuroSAFE PROOF already have tissue (biopsy) diagnosis of 
prostate adenocarcinoma and this is not the purpose of the trial.  Radiologists are 
provided with clinical details including PSA, biopsy tumour results, biopsy method, 
medical history, and any other risk factors such as family history to aid their MRI 
interpretation. Local tumour staging (according to the PIRADS anatomic division of 
the prostate at the base, the mid gland and the apex) is graded according to a 
modified 5 level Likert scale based on the risk scoring system by the European 
Society of Urological Radiology (ESUR)(26), (1 = No signs of extra-prostatic extension 
(EPE), 2 = No convincing signs of EPE, 3 = EPE might be present, 4 = EPE is likely, 5 = 
EPE is highly likely). 
Seminal vesicle invasion, lower sphincter invasion, and bladder neck invasion is 
reported as categorical ancillary reports. Subsequently, the radiologist using the 
mpMRI makes a NS recommendation for each side of the prostate for each 
participant regardless of treatment arm allocation.  The radiological NS 
recommendation will be recorded: 
 
• Nerve Sparing: Yes 
• Nerve Sparing: No 
• Digital rectal examination dependent. 
 
Image-based mpMRI surgical NS planning is aimed to assist surgeons, but NS will still 
be performed in both control and intervention arm as per the operating surgeon’s 
discretion. 

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During image based surgical NS planning, all mpMRI scans will be graded as to their 
quality according to the radiologist who reads the images.  Scoring system will be a 
1-5 Likert score.  Description of criteria on scan required to give a quality score will 
be based on the following: 
 
1. All three sequences are of insufficient quality to score any lesions. 
2. Two out of the three sequences are not diagnostic; therefore, it is not 
possible to score any lesions. 
3. It is possible to score a lesion (rule in) but it is not possible to exclude 
significant lesions (rule out). 
4. One of the sequences is not of sufficient quality.  Overall, it is possible to 
score the lesion (rule in) and rule out lesions in the background. 
5. T2, DWI (Diffusion Weighted Imaging) and DCE (Dynamic Contrast Enhanced) 
are each independently diagnostic quality.  The radiologist is able not only to 
diagnose (rule in) lesions but also to rule out lesions in the background. 
 
 Other prostate evaluation technologies and co-enrolment 
 
Prostate tissue or liquid samples pertaining to prostate cancer research of men 
enrolled in the NeuroSAFE trial can be used for other intraoperative cytopathological 
prostate evaluation technologies which will not affect clinical care or performance of 
treatment as described by this protocol (with their consent). Any ‘other’ margin 
evaluation technology assessments at participating sites must have the written 
approval from the TMG. Any additional prostate specific evaluation technologies will 
be reflected in the patient PIS and consent forms. 
 
Participating sites considering co-enrolment of NeuroSAFE PROOF patients onto 
other studies must also have written approval from the TMG. 
 
 UCLH Biobanking 
 
The NeuroSAFE PROOF team works closely with other Prostate Cancer Research 
teams, including the Molecular Diagnostics and Therapeutics Group at University 
College London. We understand the research need for successful collaboration in 
order to maximise the efficient use of research resources. As such, we will invite 
participants in the NeuroSAFE PROOF trial to consent to the use of their tissue for 
further translational cancer biology research such as that described in the PEOPLE 
study.(35) During cut up for intra-operative analysis, tissue from the prostates of 
participants will be reserved for collection by the Molecular Diagnostics and 
Therapeutics Group without compromising the performance of the NeuroSAFE 
technique, the assessment of the prostate specimen for final histological diagnosis, 
nor elongating the length of the operation/time a man spends under general 
anaesthetic. The performance of fresh tissue collection from the prostates of men 
involved will not influence decisions about their clinical care and will only be used for 
future scientific research studies. It is proposed that matched tumour and benign 

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prostate tissue will be sampled and collected for local research projects involving 
biomarkers, diagnostics, and therapeutics for prostate cancer. Methodology of these 
investigations will include but not be limited to, ex vivo cultures, genomics, and 
immunohistochemistry. All samples will be pseudonymised and all data will be 
stored securely within NHS frameworks. All tissue will be stored and tracked in 
accordance with the Human Tissue Act, with regular internal audits to ensure sample 
and data security.  
Details of the proposed tissue sampling will be described in the REC approved 
Participant Information Sheet and will be included as an additional ‘opt-in’ on the 
Informed Consent Form. A prospective participant may prefer not to consent to 
tissue sampling for molecular diagnostics and therapeutics and may still consent to 
being involved in the NeuroSAFE PROOF trial.  
 
 
 
 

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11 DATA COLLECTION 
 
Responsibility for data collection will be taken by a nominated individual. Data will 
be collected in eCRF format.  Data will be held according to the Data Protection Act 
2018 and the UK General Data Protection Regulation (GDPR). Data will be pseudo-
anonymised as necessary. Each participant will be given a trial number, and this will 
be used on all trial records. This trial number will be known by all NeuroSAFE site 
staff.  All clinical information including scans, biopsy results and blood results will be 
kept in trial records and analysed at the end of the trial. The records will be kept in a 
secure manner in the research offices with access available to named individuals 
from the trial group only. All imaging data will be held confidentially and processed 
by the named investigators for the purpose of image registration analysis, including 
the use of secure computer software for video linked proctoring between sites. The 
paper records will be retained for a minimum of 20 years after the end of the trial, 
according to the local hospital’s guidelines. 
 
 Data transfer (handling, processing and storage) 
 
In the trial, demographic data, clinical end points, surgical, pathology and imaging 
outcomes, and patient reported outcome data from questionnaires will be collected 
in accordance with the patient consent form, patient information sheet and various 
sections of this protocol. 
 
The pseudo-anonymised trial data will be appropriately sent to the trial statistician, 
please see the trial summary for statistician’s contact details, for statistical analysis.  
UCL as the sponsor, will act as the data controller. 
 
Research staff under the supervision of the principal investigator will process, store 
and dispose of the paper CRFs and data in paper form in accordance with all 
applicable legal and regulatory requirements, including the Data Protection Act 2018 
and any amendments thereto. All patient data will be stored centrally at site in a 
locked filing cabinet controlled by the principal investigator.  
 
Data entered electronically (e-CRFs) will be stored on secure servers hosted by an 
approved UCL sub-contractor - AIMES Management Services. AIMES exceed NHS 
security standards and are:  
 
• Cyber Essentials Accredited 
• Health and Social Care Network Access Compliant  
• NHS Data Security and Protection Toolkit Compliant (Standards Exceeded) 
• ISO27001:2013 Accredited 
 
UCL will remain the data controller. 
 
 
 

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 Video Collection 
 
Video recordings of all NeuroSAFE operations will be anonymised and linked to each 
patient’s unique trial NRS number. These videos will be stored on an encrypted 
external hard drive at each site in a locked filing cabinet until the end of the trial 
before being uploaded and stored in UCL’s data safe haven. These recordings are 
collected to allow for quality control review. 
 
 Health Economics Analysis 
 
A cost-utility analysis of the NeuroSAFE RARP compared to standard RARP will be 
undertaken using accepted methods. We will analyse cost-effectiveness using a 
short-run time horizon of 12 months and 2 years (within the trial period - all 
participants will be followed for at least 2 years). Costs will be assessed from the 
perspective of the NHS and PSS. Cost components included in the analysis will be the 
cost of the intervention (standard RARP and NeuroSAFE RARP); NHS costs (inpatient 
and outpatient visits, diagnostic tests, medications). Resource use data will be 
collected retrospectively from patients using questionnaires (resource use diary) at 3 
months, 6 months 12 months and 2 years. Unit costs will be taken from standard 
sources. 
 
The cost-effectiveness measures in the short-term model will be the incremental 
cost per unit of change in the QALY gained. Costs will be measured as described. 
QALYs will be calculated based on the health-related quality of life (HRQoL) collected 
using EQ5D5L and RAND36 questionnaires. Patients’ utility profiles will be 
constructed assuming a straight line between each patient’s HRQL scores at each 
follow-up point. The QALYs experienced from 3 months to 2 years will be calculated 
as the area underneath this profile. Cost-effectiveness will be calculated as the mean 
cost difference between NeuroSAFE RARP versus RARP divided by the mean 
difference in outcomes (QALYs) to give the incremental cost-effectiveness ratio 
(ICER). A sensitivity analysis will be performed to control for input parameters 
uncertainty.  
 
 Electronic Patient Reported Outcome Measures (e-PROMs) 
 
As a further COVID-19 mitigation strategy, PROM questionnaires will be sent out 
electronically over email. Clinical research teams at each site will be able to send 
patients a personalised hyperlink to their NRS number (their trial number) to input 
their questionnaire answers onto our database. Patients will only have access to 
their specific NRS profile and for that visit’s questionnaires only. These 
questionnaires contain no patient identifiable data and email addresses for these 
patients are not stored on the database. Data collected from the patients will be 
stored using the same company we currently use on a server that conforms to all 
data protection and HRA requirements. The database will contain no patient 

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identifiable data and will not be shared with anyone outside of the direct trial 
management team. 
 
To ease patient burden and for those who may not want to use a computer, 
hardcopy CRFs can be sent in the post to be filled out and returned. They will then 
subsequently be entered onto the NeuroSAFE database by the trial team. 
 

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12 STATISTICS 
 
 Sample size 
 
As of protocol version 5.0, the NeuroSAFE sample size justification has been updated 
based on the analysis of 50 patients included in the NeuroSAFE PROOF Feasibility 
Trial, which was relevant to the original version of this protocol.  25 men were 
randomly allocated to NeuroSAFE RARP and 25 allocated to standard RARP. They 
were then followed up to 12-months following treatment.  Outcomes related to 
these men will not be included in main trial analysis.  
 
Based on analysis of the feasibility trial outcomes, the primary outcome was defined 
as a comparison of erectile function recovery at 12-months between men who 
underwent NeuroSAFE RARP (intervention) vs. standard RARP (control) with 
recovery defined as an IIEF-5 score of 21 or above.  
 
The previous recruitment target according to protocol version 4.0 (August 2019) was 
for 404 men (364 evaluable).  This sample size was calculated without the benefit of 
mature functional (i.e. PROMs/IIEF-15) results related to erectile function recovery.   
 
A new sample size using the newly informed outcome data from the feasibility trial 
was prepared for protocol 5.0. The sample size is based on a 14% higher proportion 
of men with IIEF-5 score of 21 and above in the NeuroSAFE RARP (intervention) arm, 
compared to the control baseline proportion.  At 90% power, an alpha of 0.05 and a 
loss to follow up of 10%, 416 patients (374 evaluable) would be the anticipated 
recruitment target.  This sample size calculation is therefore deemed to be 
compatible with the sample size calculation submitted and used within protocol 
version 4.0 (August 2019).  Furthermore, the iDMC reviewed the sample size 
assumptions on 16th Feb 2021 and were unblinded to results from the first 150 men 
recruited to the main trial.  They advised the trial continue recruitment to the 
original number of 404 men (364 evaluable men). The iDMC will continue to review 
the recruitment target during the trial. 
 
The secondary outcome #1, the proportion of men regaining continence at 3 months 
as defined by ICIQ score of 5 or less, is powered at 89% for a 15% increase in the 
NeuroSAFE RARP (intervention) arm compared to the standard RARP (control) arm at 
3 months. 
 
Results of the feasibility trial used for sample size calculation have been redacted 
from this protocol document, as these are anticipated to be similar to interim results 
for the full powered ongoing trial, due to the internal design of feasibility trial which 
shared the same methods and centres as the main trial. The intention of restricted 
access to these preliminary results, is that these results should not influence 
recruitment to the main trial, because the feasibility trial was not powered to 
provide estimates of the primary or secondary outcomes. Full unblinded results 

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needed for sample size calculation are available in confidence for research ethics 
review and iDMC. 
 
 

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 Statistical Analysis 
 
A Statistical Analysis Plan (SAP) will be written and locked prior to analysis. 
 
In order for the NeuroSAFE PROOF trial to maintain its recruitment inertia, the 
NeuroSAFE PROOF trial was transitioned from its feasibility and pilot phases to the 
fully powered trial (covered in substantial amendment 4.0). As such, all subjects 
from the 51st patient (inclusive) onwards will be reconsented to the larger RCT.  
Patients 1-50 were treated as part of the NeuroSAFE PROOF Feasibility Trial, which 
has reported its primary outcome (recruitment).  Full 12-month reports of 
oncological and functional outcomes from the NeuroSAFE PROOF Feasibility Trial will 
be analysed as a separate cohort, per the feedback of the NeuroSAFE PROOF 
Feasibility Trial iDMC. Publication of feasibility trial results will not be before main 
trial recruitment is completed in order to maintain the equipoise of the clinicians and 
sites involved in recruitment. 
 
12.2.1 Intent to treat population 
 
The intent to treat (ITT) population, which is the primary population for efficacy, is 
defined as all men who provide written informed consent to receive the treatment. 
 
12.2.2 Per protocol population 
 
The per protocol (PP) population, which is the secondary population for efficacy, is 
defined as all ITT subjects who received the intended treatment and had no major 
protocol deviation or violation that may confound the assessment of efficacy. 
 
12.2.3 Safety population 
 
The safety population is defined as all subjects exposed to the treatment 
 
12.2.4 Statistical methods 
Primary outcome: Comparison of the unpaired proportions of men who recover 
erectile function at 12 months allocated to the NeuroSAFE intervention versus the 
control arm, based on an IIEF-5 score of 21 or more. Statistical significance will be 
established using 95% confidence intervals calculated using the Wilson method. P-
values will be reported. Further planned subgroup and sensitivity analyses will be 
conducted as detailed in section 7.2.1 
The secondary outcome #1 will use similar methods to the primary outcome. 
There will be no adjustment of p-values for secondary outcomes for multiple testing. 
STATA statistical software will be used. 
 
Due to interruption the trial due to COVID pandemic, collection of outcomes at 
particular time points has been affected, with 3- and 6-month time points being less 
regimented than anticipated. Prior to data lock, the statistical methods will be 

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reviewed. It is possible that analysis could use survival analysis of time to event 
analysis up to 12 months for both analyses, if that would make better use of data 
from multiple time points. 
Statistical methods will be reviewed on analysis of a sample of 20% of all data prior 
to data lock, after data collection and cleaning. 
 
12.2.5 Handling missing data 
Multiple imputation will be used for missing data using chained equations in STATA 
(Multiple imputation using chained equations: Issues and guidance for practice. Ian R. 
White, Patrick Royston, and Angela M. Wood. Stat Med. 2011 Feb 20;30(4):377-99.) 
For the primary outcome, multiple imputation of the ITT population will be based on 
all time points of outcome measurement as well all relevant participant covariates 
will be used. Complete case analysis (all available patient data with no imputation) 
will be reported alongside as a sensitivity analysis to the ITT analysis. 
 

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13 DATA MONITORING 
 
 Discontinuation of the trial 
 
13.1.1 Trial Discontinuation by the Sponsor 
 
The Sponsor may terminate the trial at any time if the following occur, and the 
investigator is unable to take corrective action in any of these cases: 
 
• The investigator is non-compliant with the protocol 
• The investigator is non-compliant with the regulatory requirements 
• The investigator is non-compliant with the principles of Good Clinical Practice 
as outlined in the Declaration of Helsinki and the Research Governance 
Framework (version 3.3) 
• The CRF completion is inadequate 
 
The independent Data Monitoring Committee (iDMC) will perform a quarterly review 
of the oncological outcomes reported in NeuroSAFE PROOF to ensure participant 
safety. The iDMC can meet less frequently post recruitment period. The iDMC can 
advise the Sponsor to terminate the trial early if the 3 monthly BCR safety measure 
shows an increased incidence in the NeuroSAFE arm (this would be defined as 
incidences p<0.01). 
 
Salvage treatment should only be started after discussion and agreement at SMDT. 
 
13.1.2 Discontinuation of Trial for an Individual Patient 
The criteria for discontinuing the trial in the case on individual patients are: 
 
Inter-current illness 
Any illness, which in the judgment of the investigators would affect the assessments 
of clinical status to a significant degree 
 
Request by the patient 
It is the patients right to request discontinuation of their participation in the trial. If 
this request is made, it will be respected and will not affect the patient’s ability to 
receive medical care from the investigators now or in the future. 
 
Discontinuation of attendance at an investigating site 
Efforts should be made to maintain the investigations schedule and continue follow-
up, even if patients no longer attend the participating institution. 
 
 
 

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  Quality assurance 
In order to ensure the quality of the data collected in the trial, the principal 
investigator will provide means for data monitoring and QC of the database. Data 
will be handled according to regulatory requirements and be protected according to 
EU Law Enforcement Directive EU2016/680 (which is now incorporated into UK 
GDPR) and the Data Protection Act 2018 as well as local data protection 
requirements.  
 
NeuroSAFE PROOF collects detailed information on histological surgical margin 
status for safety and future publication purposes. Descriptions of histological 
diagnosis can differ between sites due to differing interpretations of histological 
analyses. In order to ensure standard, consistent reporting in line with quality 
assurance, we will request anonymised pathology reports to ensure accurate, 
standardised reporting in the trial database. This will occur across both arms of the 
trial. These reports will be sent electronically in a secure manner (e.g. an NHS.net 
account) to the NeuroSAFE clinical trial manager at UCL. The reports will be stored in 
a secure environment that conforms to NHS Digital’s data and protection toolkit. The 
trial manager will de-identify the reports and assign them a unique identifier before 
sending them for review by a UCLH pathologist. Findings from this quality assurance 
review will be collated and discussed with all participating pathologists after the last 
operation (in either arm) has been completed. The reports will be compared to the 
UCLH pathology reporting standard operating procedure document.  
 
 Assessment of safety 
 
Adverse Event Definitions 
Adverse Event 
Any untoward medical occurrence in a subject including occurrences, which are not 
necessarily caused by or related to the intervention 
 
Adverse Reaction 
Any untoward and unintended response in a subject, which is related to the 
intervention 
 
Unexpected Adverse Reaction 
An adverse reaction, the nature and severity of which is not consistent with the trial 
intervention(s) 
 
Serious Adverse Event/Reaction (SAE/SAR) 
Any untoward medical occurrence that: 
 
1. Is a life threatening illness or injury 
2. Is a permanent impairment to a body structure or function 
3. Is a condition requiring hospitalisation or increased length of existing 
hospitalisation (except hospitalisation for planned admission unrelated to the 
intervention, urinary retention requiring catheterisation) 

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4. Is a condition requiring otherwise unnecessary medical or surgical 
intervention and which might have led to death or serious deterioration in 
health had suitable action or intervention not taken place. 
5. Led to foetal distress, foetal death or a congenital abnormality or birth defect 
6. Might have led to any of the above 
 
Suspected Unexpected Serious Adverse Reaction 
All suspected adverse reactions related to the intervention that is both unexpected 
and serious. 
 
Adverse Events Classification 
The definitions used to describe the relationship between the adverse event and the 
trial interventions are the following: 
 
Unrelated 
An adverse event that is definitely not related to the intervention. 
 
Unlikely 
An adverse event for which an alternative explanation is more likely e.g. concurrent 
drug(s), concomitant disease(s), and/or the relationship in time suggests that a 
causal relationship is unlikely. 
 
Possible 
An adverse event that might be due to the intervention. An alternative explanation 
e.g. concurrent drug(s), concomitant disease(s), is inconclusive. The relationship in 
time is reasonable; therefore, the causal relationship cannot be excluded. 
 
Probable 
An adverse event that might be due to the intervention. The relationship in time is 
suggestive (e.g. confirmed by rechallenge). An alternative explanation is less likely 
e.g. concurrent drug(s), concomitant disease(s). 
 
Very likely 
An adverse event, that is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation e.g. concurrent drug(s), 
concomitant disease(s). The relationship in time is very suggestive (e.g. it is 
confirmed by de-challenge and re-challenge). 
 
Un-assessable 
It is not possible to assign the reaction to any of the above categories because of 
insufficient, pending, or contradictory information. Further information is requested 
in order to lead to an attribution of causality. 
 
 

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 SAE Reporting 
 
All serious adverse events (SAEs) must be reported to the NCITA Clinical Trials Unit 
within 24 hours of the Investigator’s knowledge of the event (except for those that 
are identified in the protocol as not needing immediate reporting) via the 
appropriate SAE form. The trials unit will notify the main Research Ethics Committee 
and sponsor within 15 days of the Chief Investigator becoming aware of the event.  
 
Those events arising will be reported on a three-monthly basis to the TMG and 
TSC/iDMC in a summary format, to include: 
• The number of serious adverse events in a tabular format laying out the 
percentages of each type of serious events with an indication as to how many 
of those are thought to be related to the trial intervention.  
• The total number of patients recruited during that same 3-month period and 
in total.  
• Clavien-Dindo classified complications of 3 or more will be anonymised and 
blinded before being submitted to the TMG for central grading and review of 
site.  
 
 Reporting Requirements 
 
In line with the Health Research Authority guidance on non-CTIMP trials, only 
reports of SAEs that are listed below will require reporting to the CTU (and 
subsequently sponsor & ethics): 
 
• Related to the trial (i.e. they resulted from the use of the NeuroSAFE 
technique) and 
• Unexpected (that is not listed in section 13.7 – Expected Adverse Events) 
 
 
 

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 Flow of SAE Reporting 
 
 
 
 
AE occurs 
Assign Severity Grade 
Was the event Serious? 
Was the event an 
Other Notifiable 
event?   
No 
No 
*CTU will forward unexpected and related SAEs to REC & Sponsor 
Yes 
Yes 
Yes 
No 
Submit SAE form to CTU* within 5 
working days 
Record in medical records 
Record in medical 
records and CRF 
(if applicable) 
Is the event specified as an adverse event which does not require immediate reporting as an SAE?  
Record in medical records, CRF 
(and AE Log if required)  
Complete an SAE report form 
SAE Reporting: 
Please email the completed SAE form to: uclh.ncita.sae@nhs.net 

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 Expected Adverse Events 
 
The following are expected adverse events following a radical prostatectomy with 
their corresponding likelihoods (31-34).  These should be recorded in the patient’s 
medical records but do not need an Adverse Event CRF to be submitted. These will be 
recognised as expected for trial treatment. 
 
Expected adverse events: 
  
Intra-operative 
Bleeding – (requiring transfusion) - 1% 
Visceral injury requiring laparotomy – 1% 
Vascular injury requiring laparotomy – 1% 
Cardiac event (Myocardial infarction 0.1%, Atrial Fibrillation 1.6%, syncope 1.2%). 
 
Early post-operative 
Wound related problems; infection (2%), incisional hernia (2%) 
Thromboembolic event (deep vein thrombosis or pulmonary embolus 0.8%)  
Lymphoedema – 1% (higher incidence when eLND performed) 
Anaesthetic problems requiring admission to intensive care unit (2%) 
Gastrointestinal; ileus/damage to bowel requiring temporary colostomy (0.5%) 
Seroma – 1% 
Urethral Stricture – 2% 
 
Expected longer term outcomes or side effects of surgery 
Urinary incontinence (temporary) –100% 
Erectile dysfunction – (up to 100%) 
Long term urine leak – 10%  
Adjuvant therapies (including radiotherapy and ADT) – 30% 
 
13.7.1 Notification of Death 
 
As with all major surgery there is also a risk of death.  The risk of death with either of 
these surgical interventions is thought to be less than one in a hundred. Any deaths 
including deaths unrelated to the treatment will be recorded on the CRF/database. 
 
13.7.2 Period of observation 
For the purpose of this trial, the period of observation of serious adverse events 
extends from consent to 90 days post op as it unlikely any SAEs past this point will be 
related to surgery. This will reduce site reporting workload. Trial follow up should 
continue according to schedule once the SAE is resolved, if applicable. The trial will, 
however, continue to collect death SAEs throughout per section 13.7.1. 
 
 
 

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14 ETHICAL CONSIDERATIONS 
 
The Chief Investigators will take primary responsibility for the conduct of the trial in 
accordance with the World Medical Association Declaration of Helsinki and 
subsequent amendments, and the conduct will conform to ICH GCP guidelines and 
the Research Governance Framework Guidelines. 
 
Subject Information and Informed Consent: The patient’s consent to participate in 
the trial should be obtained after a full explanation has been provided of the 
procedures to be given. All subjects must sign and personally date an approved 
informed consent after having received detailed written and verbal information 
about the reason, nature and possible risks associated with the research program. 
Patients should be given sufficient time after being given the trial patient 
information sheet to consider and discuss participation in the trial with family and 
friends. Patients will always be asked to sign a consent form. One copy will be given 
to the patient, one copy will be kept with patient’s hospital notes and one copy 
should be kept in the local investigator site file. 
 
The subject must be made aware and agree that personal information may be 
scrutinized during monitoring and audit by competent authorities and properly 
authorized persons. However, personal information will be treated as strictly 
confidential and will not be publicly available. 
 
The right of the patient to refuse to participate in the trial without giving reasons 
must be respected. After the patient has entered the trial, the clinician must remain 
free to manage the patient however he/she feels fit to suit the best interest of the 
patient, regardless of the protocol. Similarly, the patient must remain free to 
withdraw from the trial at any time without giving reasons and without prejudicing 
any further treatment or the standard of care received. 
 
An Institutional Review Board and/or 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.  
 
Specific Ethical Issues 
None 
 
 

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15 FINANCING AND INSURANCE 
 
University College London holds insurance against claims from participants for injury 
caused by their participation in the trial. Participants may be able to claim 
compensation if they can prove that UCL has been negligent. However, as this trial is 
being carried out in a hospital, the hospital continues to have a duty of care to the 
participant of the trial.  University College London does not accept liability for any 
breach in the hospital’s duty of care, or any negligence on the part of hospital 
employees. This applies whether the hospital is an NHS Trust or otherwise.   
 
Participants may also be able to claim compensation for injury caused by 
participation in this trial without the need to prove negligence on the part of 
University College London or another party.  Participants who sustain injury and wish 
to make a claim for compensation should do so in writing in the first instance to the 
Chief Investigator, who will pass the claim to the Sponsor’s Insurers, via the 
Sponsor’s office. 
 
 
The NIHR Research for Patient Benefit, Jon Moulton Charitable Foundation Trust and 
St. Peters Trust fund this trial. 
 
 
 
 

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16  REPORTING AND DISSEMINATION 
 
Results of scientific interest from the trial and any parallel translational work will be 
submitted for consideration for presentation to professional and scientific meetings, 
and publications in peer reviewed professional and scientific literature. They may 
also be included in theses and dissertations. 
Any submissions are to have authorisation from the chief investigator and co-
investigators upon review by the TMG. Authorship will be determined on a per paper 
basis. The chief investigator will have final say if agreement cannot be reached. 
 
 Patient and Public Involvement  
 
Patient feedback on the design of the trial was obtained. The PPI events were 
supported by Macmillan Cancer (Charity no 261017) and Orchid (Charity no 
1080540). Participants, patients and their families were asked specifically about the 
level of blinding, the burden of follow-up appointments and priorities in their 
recovery from RALP.  
 
Following their feedback, NeuroSAFE PROOF now informs men following surgery of 
their NS status, though blinding to allocation status (intervention or 
control) is maintained. Patient representatives sit on both the trial steering 
committee (TSC) and the Data Monitoring Committee (iDMC) contributing to the 
oversight of the management of the trial. The trial is also funded by National 
Institute for Healthcare Research for Patient Benefit (NIHR RfPB) stream, which has 
patient members on their decision panels.  
 
 
 NeuroSAFE PhD report 
NeuroSAFE PROOF will constitute a substantial part of the PhD research degree for 
Mr Eoin Dinneen. Mr Dinneen is enrolled at University College London within the 
Division of Surgery and Interventional Sciences. His supervisors are Professor John 
Kelly, Professor Shonit Punwani and Mr Greg Shaw (Chief Investigator of NeuroSAFE 
PROOF). Mr Dinneen anticipates finishing his PhD and submitting his thesis in July 
2021. Mr Dinneen has been heavily involved in the design and execution of the both 
the feasibility and the full-scale NeuroSAFE PROOF trial. Particularly, Mr Dinneen has 
been influential in the establishment of the NeuroSAFE PROOF feasibility trial, day-
to-day running of the trial, designing the full- scale NeuroSAFE PROOF trial, writing 
protocol versions 2-5, writing and submitting the protocol manuscripts for peer 
review and publication, co-ordinating PPI on behalf of the NeuroSAFE PROOF team, 
selecting the primary endpoint, standardisation of reporting of crucial elements of 
the trial methodologies (such as the role of MRI reporting, the surgical response to 
the positive NeuroSAFE, statistical handling of the NS status of surgery, and health 
economics analysis). Mr Dinneen will write his thesis on evaluation of extra-prostatic 
extension and surgical margin status in men undergoing RARP. This work will rely 
heavily upon the skills and techniques developed as part of his role in NeuroSAFE 

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PROOF. Given that the NeuroSAFE PROOF trial will form a significant part of Mr 
Dinneen’s PhD thesis, it is intended that Mr Dinneen be given confidential, unblinded 
access to data and results of statistical analyses. This will mean that the thesis will be 
made open access after an embargo period (determined by the CI), to enable first 
publication of the trial results in a journal. 
 

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17  REFERENCES 
 
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D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick 
GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation 
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Shaw GL, Thomas BC, Dawson SN, Srivastava G, Vowler SL, 
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Thalgott M, et al. Intraoperative frozen section monitoring during nerve-sparing 
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bundles and its effect on oncologic and functional outcome. World journal of urology. 
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Tewari AK, Srivastava A, Huang MW, Robinson BD, Shevchuk MM, Durand 
M, et al. Anatomical grades of nerve sparing: a risk-stratified approach to neural-
hammock sparing during robot-assisted radical prostatectomy (RARP). BJU Int. 
2011;108(6 Pt 2):984-92. 
26. 
Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, Villeirs G, et al. 
ESUR prostate MR guidelines 2012. Eur Radiol. 2012;22(4):746-57. 
27. 
Mehralivand S, Shih JH, Harmon S, Smith C, Bloom J, Czarniecki M, et al. A 
Grading System for the Assessment of Risk of Extraprostatic Extension of Prostate 
Cancer at Multiparametric MRI. Radiology. 2019;290(3):709-19. 
28. 
Roethke MC, Lichy MP, Kniess M, Werner MK, Claussen CD, Stenzl A, et al. 
Accuracy of preoperative endorectal MRI in predicting extracapsular extension and 
influence on neurovascular bundle sparing in radical prostatectomy. World J Urol. 
2013;31(5):1111-6. 
29. 
Cornud F, Rouanne M, Beuvon F, Eiss D, Flam T, Liberatore M, et al. 
Endorectal 3D T2-weighted 1mm-slice thickness MRI for prostate cancer staging at 

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1.5Tesla: should we reconsider the indirects signs of extracapsular extension 
according to the D'Amico tumor risk criteria? Eur J Radiol. 2012;81(4):e591-7. 
30. 
Kilminster S, Muller S, Menon M, Joseph JV, Ralph DJ, Patel HR. Predicting 
erectile function outcome in men after radical prostatectomy for prostate cancer. BJU 
international. 2012;110(3):422-6. 
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Fridriksson JO, Folkvaljon Y, Lundstrom KJ, Robinson D, Carlsson S, Stattin 
P. Long-term adverse effects after retropubic and robot-assisted radical 
prostatectomy. Nationwide, population-based study. J Surg Oncol. 2017;116(4):500-
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Comprehensive prospective comparative analysis of outcomes between open and 
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2008;179(5):1811-7; discussion 7. 
34. 
Yaxley JW, Coughlin GD, Chambers SK, Occhipinti S, Samaratunga H, 
Zajdlewicz L, et al. Robot-assisted laparoscopic prostatectomy versus open radical 
retropubic prostatectomy: early outcomes from a randomised controlled phase 3 
study. Lancet. 2016;388(10049):1057-66 
35. Heavey S, Costa H, Pye H, et al. PEOPLE: PatiEnt PrOstate SamPLes for 
REsearch, a Tissue Collection Pathway Utilizing Magnetic Resonance Imaging Data 
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18 ROLES AND RESPONSIBILITIES 
These membership lists are correct at the time of writing; please see terms of reference 
documentation in the Trial Master File for current lists. 
 
Protocol contributors 
Name 
Affiliation 
Role  
Mr Greg Shaw 
UCLH 
Chief Investigator and Lead Clinician 
Dr Ricardo Almeida Magana 
UCLH 
Urology clinical fellow 
Ms Chris Brew-Graves 
UCL 
NeuroSAFE co-applicant 
Mr Nick Roberts 
UCL/UCLH 
Trial Manager  
Professor Sue Mallett 
UCL 
Trial Statistician 
 
Trial Team 
Name 
Affiliation 
Role and responsibilities 
Mr Greg Shaw 
UCLH 
Chief Investigator and Lead Clinician 
Prof John Kelly 
UCL 
Co-Investigator 
Dr Alex Freeman 
UCLH 
Co-Investigator 
Mr Neil Oakley 
Royal Hallamshire 
Hospital 
Co-Investigator 
Prof Raj Persad 
Southmead Hospital 
Co-Investigator 
Mr Jon Aning 
Southmead Hospital 
Co-Investigator 
Mr Imran Ahmad 
Queen Elizabeth 
University Hospital 
Co-Investigator 
Mr Thomas Walton 
Nottingham University 
Hospitals NHS Trust 
Co-Investigator 
Dr Norman Williams 
SIG 
NeuroSAFE Co-applicant 
Ms Chris Brew-Graves 
UCL 
NeuroSAFE Co-applicant  
Mr Nick Roberts 
UCL 
Trial Manager 
Dr Ricardo Almeida Magana 
UCLH 
Urology clinical fellow 
Dr. Aiman Haider 
UCLH 
Pathology clinical fellow 
Dr. Elena Pizzo 
UCL 
Health Economist 
Professor Sue Mallett 
UCL 
Trial Statistician 
 
Trial Steering Committee 
Name 
Affiliation 
Mr Greg L. Shaw 
Chief Investigator and Lead Clinician 
Mr Tim Lane 
Chair 
 
Mr Abay Mulatu  
Patient representative 
Mr Ben Lamb 
Independent clinician 
Dr Helen Parsons 
Independent statistician 
 
Independent Data Monitoring Committee  
Name 
Affiliation 
Mr Alastair Lamb  
Independent clinician for safety 
Prof Jane Warwick 
Chair/ Independent biostatistician 
Mr Roy Jeans 
Patient representative