Fully Hybrid 18F-PSMA PET/MRI as One-stop Approach for the Diagnosis of Clinically Significant Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: IRCCS San Raffaele

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CLINICAL TRIAL PROTOCOL 
 
Title: Fully hybrid 18F-PSMA PET/MRI as one-stop approach for the diagnosis of clinically 
significant prostate cancer 
 
 
 
 
DISCLAIMER 
This material is strictly private, confidential and property of OSR (The Sponsor). Its contents must not be disclosed or 
used except as authorized in writing by the Sponsor. 
 
 
Protocol Acronym/Number 
RF-2021-12372278 
EudraCT number 
2022-003905-31 
Other Protocol Identifiers 
NA 
Version 
v2.0 
Date 
30 GEN 2023 
 
 
Sponsor 
IRCCS Ospedale San Raffaele 
Authorized Sponsor Representative Arturo Chiti, Prof 
Director 
U.O. of Nuclear Medicine 
Funding Sponsor or Source(s) 
Italian Ministry of Health 
Principal Investigator 
Maria Picchio, MD 
Professor 
U.O. of Nuclear Medicine 

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VERSION HISTORY 
 
 
 
 
Protocol 
version n. 
Reason of changes 
Date issued 
v1.0 
First Version submitted to the OSR Ethics Committee (EC) 
and AIFA 
23 NOV 2022 

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PROTOCOL SIGNATURE PAGE 
 
Trial Title: Fully hybrid 18F-PSMA PET/MRI as one-stop approach for the diagnosis of clinically 
significant prostate cancer 
Protocol Acronym/Number: RF-2021-12372278 
EudraCT Number: NA 
Protocol Version and Date: v2.0 30 GEN 2023 
 
The undersigned has read and understood all the aspects of the protocol detailed within this 
document and agrees to supervise and conduct the trial in accordance with the protocol, Guideline 
for Good Clinical Practice ICH E6 (R2), Declaration of Helsinki, and all applicable regulatory 
requirements. 
 
 
Maria Picchio 
 
 
 
U.O. of Nuclear Medicine 
 
 
Principal 
Investigator Name 
 
Signature 
 
Affiliation 
 
Date 
 
 
 
 
 
 
 
Arturo Chiti 
 
 
 
U.O. of Nuclear Medicine 
 
 
Authorized Sponsor 
Representative 
Name 
 
 
 
 
Signature 
 
Affiliation 
 
Date 

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TABLE OF CONTENTS 
 
1. 
KEY TRIAL CONTACTS........................................................................................................... 7 
2. 
SYNOPSIS ................................................................................................................................ 9 
3. 
ABBREVIATIONS AND DEFINITIONS .................................................................................. 12 
3.1. 
Abbreviations ............................................................................................................... 12 
3.2. 
Definitions .................................................................................................................... 13 
4. 
BACKGROUND AND RATIONALE ........................................................................................ 14 
5. 
RISK/BENEFIT ASSESSMENT ............................................................................................. 14 
5.1. 
Known Potential Risks ................................................................................................. 14 
5.2. 
Known Potential Benefits ............................................................................................. 15 
5.3. 
Assessment of Risks and Benefits ratio ...................................................................... 15 
6. 
OBJECTIVES AND ENDPOINTS .......................................................................................... 15 
7. 
EFFICACY AND SAFETY CRITERIA .................................................................................... 16 
7.1. 
Efficacy Criteria ............................................................................................................ 16 
7.2. 
Safety Criteria .............................................................................................................. 16 
8. 
TRIAL DESIGN ....................................................................................................................... 16 
8.1. 
Study duration .............................................................................................................. 17 
9. 
TRIAL POPULATION ............................................................................................................. 18 
9.1. 
Trial Participants .......................................................................................................... 18 
9.2. 
Inclusion Criteria .......................................................................................................... 18 
9.3. 
Exclusion Criteria ......................................................................................................... 18 
9.4. 
Screening Failures ....................................................................................................... 18 
10. 
TRIAL INTERVENTIONS .................................................................................................... 18 
10.1. 
Investigational Medicinal Product(s) (IMP) Description .............................................. 18 
10.2. 
Treatment Schedule .................................................................................................... 18 
10.3. 
Method for Assigning Subjects to Treatment Groups ................................................. 19 
10.4. 
Blinding of IMPs ........................................................................................................... 19 
10.5. 
Receiving and Storage of IMP ..................................................................................... 19 
10.6. 
Preparation, Administration and Accountability of the Trial Treatments..................... 19 
10.7. 
Compliance with Trial Treatment ................................................................................. 20 
10.8. 
Concomitant Medication .............................................................................................. 20 
10.9. 
Rescue Therapy........................................................................................................... 20 
10.10. 
Post-trial Treatment ..................................................................................................... 20 
10.11. 
Other Treatments (NIMPS: PeIMP - ReTNIMP) ......................................................... 20 

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10.12. 
Other Interventions ...................................................................................................... 21 
11. 
TRIAL PROCEDURES........................................................................................................ 22 
11.1. 
Informed Consent ........................................................................................................ 23 
11.2. 
Subject Recruitment and Screening ............................................................................ 23 
11.3. 
Subject Identification .................................................................................................... 23 
11.4. 
Randomization and Blinding ........................................................................................ 24 
11.5. 
Baseline Assessments................................................................................................. 24 
11.6. 
Visits and Follow Up .................................................................................................... 24 
11.7. 
Definition of End of Study ............................................................................................ 24 
11.8. 
Premature termination or suspension of a trial ........................................................... 24 
12. 
DISCONTINUATION AND WITHDRAWAL ........................................................................ 25 
12.1. 
Discontinuation of Trial Intervention ............................................................................ 25 
12.2. 
Participant Discontinuation/Withdrawal from the Trial ................................................ 25 
12.3. 
Lost to Follow-Up ......................................................................................................... 25 
13. 
SAMPLE HANDLING .......................................................................................................... 25 
14. 
PATIENT SAFETY .............................................................................................................. 25 
14.1. 
Safety profile of the IMP .............................................................................................. 26 
14.2. 
Adverse Event Definitions ........................................................................................... 26 
14.3. 
Adverse Event Severity Grading Scale ....................................................................... 26 
14.4. 
AE Attribution Scale ..................................................................................................... 27 
14.5. 
Procedures for Reporting Adverse Events .................................................................. 27 
14.6. 
Reporting Procedures for Serious Adverse Events .................................................... 27 
14.7. 
Follow-up of AE / SAE / ADR ...................................................................................... 28 
14.8. 
SUSAR Reporting ........................................................................................................ 28 
14.9. 
Development Safety Update Reports .......................................................................... 28 
14.10. 
Unblinding Procedures ................................................................................................ 28 
15. 
DATA MANAGEMENT ........................................................................................................ 28 
15.1. 
Definition of source data and source documents ........................................................ 28 
15.2. 
Documentation of data Case Report Forms (CRFs) ................................................... 29 
15.3. 
Data Recording and Record Keeping.......................................................................... 29 
15.4. 
Data Protection ............................................................................................................ 29 
16. 
STATISTICS ........................................................................................................................ 29 
16.1. 
Description of Statistical Methods ............................................................................... 29 
16.2. 
Sample Size Determination ......................................................................................... 30 

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16.3. 
Analysis Populations .................................................................................................... 30 
16.4. 
Interim Analysis............................................................................................................ 30 
16.5. 
Stopping Rules ............................................................................................................. 30 
17. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................ 30 
17.1. 
Responsibilities of the Investigator(s).......................................................................... 30 
17.2. 
Ethics Committee (EC) Approvals ............................................................................... 31 
17.3. 
Other Ethical Considerations ....................................................................................... 31 
18. 
QUALITY ASSURANCE AND QUALITY CONTROL ......................................................... 31 
18.1. 
Monitoring .................................................................................................................... 31 
18.2. 
Deviation from study protocol ...................................................................................... 31 
18.3. 
Data and Safety Monitoring Board .............................................................................. 32 
18.4. 
DSMB roles and responsibilities .................................................................................. 32 
19. 
FINANCE AND INSURANCE ............................................................................................. 32 
19.1. 
Funding ........................................................................................................................ 32 
19.2. 
Patient Insurance ......................................................................................................... 32 
19.3. 
Contractual arrangements ........................................................................................... 32 
20. 
END OF CLINICAL TRIAL .................................................................................................. 32 
20.1. 
SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL ....................................... 33 
21. 
INTELLECTUAL PROPERTY ............................................................................................. 33 
22. 
PUBLICATION POLICY ...................................................................................................... 33 
23. 
REFERENCES .................................................................................................................... 33 
24. 
APPENDIX A:  AMENDMENT HISTORY ........................................................................... 34 
25. 
APPENDIX B:  LIST OF CLINICAL SERVICES / LABORATORIES ................................. 34 
 
 
 

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1. KEY TRIAL CONTACTS 
 
Sponsor 
IRCCS Ospedale San Raffaele 
Via Olgettina, 60 
20132 – Milano, Italy  
Authorized Sponsor 
Representative 
Arturo Chiti 
Director  
U.O. of Nuclear Medicine 
Ospedale San Raffaele 
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26432709 
Email: chiti.arturo@hsr.it 
Principal Investigator 
Maria Picchio, MD 
Professor  
U.O. of Nuclear Medicine 
Ospedale San Raffaele 
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26436117 
Email: Picchio.maria@hsr.it 
Sub-investigator(s) 
Paola Vittoria Scifo, PhD 
U.O. of Nuclear Medicine 
Ospedale San Raffaele 
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26432054 
Email: scifo.paola@hsr.it 
 
Armando Stabile, MD 
Department of Urology 
Ospedale San Raffaele 
Via Olgettina 60 – 20132 – Milano, Italy 
Tel 02-26433618 
Email: stabile.armando@hsr.it 
 
Giulia Cristel, MD 
Department of Radiology 
Ospedale San Raffaele 
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26432489 
Email: cristel.giulia@hsr.it 
 
Ana Maria Samanes Gajate, MD 
U.O. of Nuclear Medicine 
Ospedale San Raffaele 
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26432113 

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Email: samanesgajate.anamaria@hsr.it 
Study Clinical Unit  
Maria Picchio, MD 
Professor  
U.O. of Nuclear Medicine 
Ospedale San Raffaele 
Via Olgettina, 60 – 20132 – Milano, Italy 
Tel 02-26436117 
Email: Picchio.maria@hsr.it 
Funding source(s) 
Italian Ministry of Health   
Pharmacovigilance 
Contact 
OSR Clinical Trial Pharmacy 
Email: farmacia.trialsclinici@hsr.it  
Monitoring Contact 
Clinical Trial Center – OSR  
Email: monitoring.ctc@hsr.it  
 
 

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2. SYNOPSIS  
 
Trial Title 
Fully hybrid 18F-PSMA PET/MRI as one-stop approach for the 
diagnosis of clinically significant prostate cancer 
Protocol 
Acronym/Number 
RF-2021-12372278 
Protocol Version 
and Date 
v2.0, 30 GEN 2023 
EudraCT number 
NA 
Sponsor  
IRCCS Ospedale San Raffaele 
Via Olgettina 60 – 20132, Milan, Italy 
Funding Source(s) 
Italian Ministry of Health 
Principal 
Investigator 
Maria Picchio, U.O. of Nuclear Medicine 
Trial Description 
This project aims to evaluate the role of fully hybrid PET/MRI with 18F-
PSMA and multiparametric MR imaging (mpMRI) as 
one-stop approach for the diagnosis of clinically significant prostate 
cancer (csPCa). 
Our main hypothesis is that adding 18F-PSMA PET to mpMRI prior to 
biopsy, will reduce the number of false negative findings, while at the 
same time, allowing also to reduce the number of unnecessary 
prostate biopsies in patients with low-risk, clinically indolent PCa. 
 
Primary 
Secondary 
Objectives  
To assess the 
accuracy and the 
predictive value of fully 
hybrid 18F-PSMA 
PET/MRI for the 
diagnosis of csPCa 
1) To compare the proportion of csPCa 
missed by 18F-PSMA PET scan or 
mpMRI alone 
2) To report the reduction in the 
detection of clinically insignificant 
PCa when combining mpMRI and 
18F-PSMA PET, and consequently 
the proportion of unnecessary 
biopsies potentially spared. 
 
Endpoints  
Diagnostic accuracy 
measured with 
sensitivity, specificity, 
positive and negative 
predicted value 
1) The number of csPCa missed by 
PET and MR imaging when read 
independently 
2) Only in patients with positive mpMRI 
and negative 18F-PSMA PET: The 
proportion of clinically insignificant 
PCa 
Time point(s) 
day 0: 18F-PSMA 
PET/MRI 
day 90 (+/- 90): 
prostate biopsy 
 
Phase 
Phase II 
Trial Design 
Monocentric, single-arm, prospective  

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Trial Population 
Men with clinical suspicion of csPCa. 
Inclusion Criteria 
1) Men at least 18 years of age referred with clinical suspicion of 
prostate cancer candidate for prostate biopsy 
2) Feasibility to undergo all procedures listed in protocol 
3) Ability to provide written informed consent 
Exclusion Criteria 
1) Prior diagnosis of prostate cancer 
2) Contraindication to MRI (e.g. claustrophobia, pacemaker, estimated 
GFR lower or equal to 50mls/min) 
3) Contraindication to prostate biopsy 
Intervention(s) 
 
IMP(s) 18F-PSMA, 4 MBq/Kg, intravenous administration 
NIMP(s) Not applicable. 
Other 
intervention(s) Prostate biopsy guided by imaging findings 
Comparator  Not applicable. 
Safety Criteria 
Patients’ compliance. 
Efficacy Criteria 
Diagnostic accuracy  
Sample Size  
167 patients, all enrolled at OSR 
Statistical Design 
Diagnostic accuracies of 18F-PSMA PET and mpMRI will be 
calculated by means of sensitivity: true positive/(true positive + false 
negative); specificity: true negative/(false positive + true negative); 
PPV: true positive/(true positive + false positive); and NPV: true 
negative/(true negative + false negative) using the prostate biopsy 
result as reference standard 
List of Enrolling 
Sites (if applicable) 
Not applicable. 
Duration of the 
Trial 
Duration of enrollment: 27 months 
Duration of treatment: two hours per patient (over 27 months) 

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Duration of total follow-up: NA (after biopsy there will not be further 
visits) 
Duration of total trial period: 36 months 

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3. ABBREVIATIONS AND DEFINITIONS 
3.1. Abbreviations 
ADR  
Adverse drug reaction 
AE 
Adverse event 
CIOMS 
Council for International Organization of Medical Science 
CRF 
Case Report Form 
CRO  
Contract Research Organization 
CTA 
Clinical Trial Application 
DSMB 
Data and Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
GCP 
Good Clinical Practice 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
LVSL 
Last Visit of Last Subject  
MedDRA 
Medical Dictionary for Regulatory Activities 
NIMP 
Non-Investigational Medicinal Product 
PeIMP 
Products equivalent to the IMP 
PI 
Principal Investigator 
QP 
Qualified Person 
ReTNIMP 
Regardless to Trial NIMP 
SAE 
Serious Adverse Event 
SAR  
Serious Adverse Reaction 
SDR 
Serious Drug Reaction 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
csPCa 
clinically significant prostate cancer 
PSA 
prostate specific antigen 
EAU 
European Association of Urology 

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mpMRI 
multiparametric magnetic resonance imaging 
PSMA 
prostate specific membrane antigen 
PET 
positron emission tomography 
ROI 
region of interest 
OSR 
Ospedale San Raffaele 
ROC 
Receiver operating characteristics 
 
 
 
3.2. Definitions 
Not applicable. 
 
 
 

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4. BACKGROUND AND RATIONALE 
Prostate cancer (PCa) is the second most common cancer in men, with 1,414,259 new cases in 
2020, accounting for 15.1% of all cancer diagnoses within the male population (1). The current 
EAU Guidelines for PCa recommend performing mpMRI before prostate biopsy in men with clinical 
suspicion of PCa (2). However, the accuracy of mpMRI in detecting csPCa remains suboptimal 
and a significant proportion of unnecessary biopsies are performed in men with suspicious lesions 
on mpMRI (3). Several efforts were made to identify new diagnostic strategies to implement 
mpMRI performances. The use of PSMA PET, widely implemented for clinical management of 
PCa both in recurrent and primary setting, has recently gained interest for diagnostic purposes. In 
296 men with suspicion of PCa, the combined use of 68Ga-PSMA PET and mpMRI for PCa 
diagnosis showed improved sensitivity and negative predicted value for csPCa (4). Based on 
these results, the combination of mpMRI and 68Ga-PSMA PET might reduce the number of 
prostate biopsies required to diagnose csPCa. In this prior study, mpMRI and 68Ga-PSMA PET 
have been acquired and interpreted separately, with the risk of introducing potential confounders. 
Moreover, imaging-guided targeted biopsies were not systematically performed. 
In this project, the role of hybrid PET/MRI with 18F-PSMA will be evaluated in PCa diagnosis. The 
major advantages of this innovative technology are the simultaneous acquisition of PET and 
mpMR imaging by using a fully hybrid PET/MRI scan and the use of 18F-PSMA with improved 
spatial resolution compared to 68Ga-PSMA, due to its lower positron energy. 
 
5. RISK/BENEFIT ASSESSMENT 
5.1. Known Potential Risks 
A potential risk of this study is patients' compliance regarding the execution of a PET exam in 
addition to the standard of care MRI and the prolonged scan time. The scan will be performed 
simultaneously on a dedicated hybrid PET/MRI whole body scanner and additional data regarding 
potential disease extension will be collected concomitantly. Longer execution time, though, will 
offer added value for describing disease both to the patient as well as for the scope of this study. 
The side effects of contrast medium for MRI are very low (standard of care), as are those 
documented by internal unpublished data on the use of 18F-PSMA. Our goal is also to optimize 
these dedicated PET/MRI acquisition protocols in terms of duration, hopefully increasing patient 
compliance. The interventions proposed in this trial are aligned with what suggested by the EAU 
Guidelines for prostate cancer diagnosis. Specifically, all patients will undergo mpMRI as 
recommended by EAU guidelines. In addition to mpMRI, all patients will undergo a concomitant 
18F-PSMA PET whose results will be evaluated jointly with those of the mpMRI during the same 
diagnostic session. Therefore, participants will be offered the diagnostic gold standard plus 
additional 18F-PSMA PET, whose use in the diagnostic pathway has been already proposed (4,5). 
Regarding the toxicity and radioactive exposure associated with the use of radionuclides PSMA, 
several studies have demonstrated the low exposure to radiation and showed no adverse effects 
or toxicity (6). All patients will then undergo a 12-core SBx as also recommended by the EAU 
guidelines plus TBx in case of either 18F-PSMA PET or mpMRI would show suspicious lesion/s, 
adverse events (AE) will be recorded by a member of the research team or clinical team on an AE 
report form. All serious AE (SAE) will be recorded on a SAE report form. Both AE and SAE should 
be recorded in the medical notes. 

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5.2. Known Potential Benefits 
In this study we will implement and assess a novel 18F-PSMA PET targeted software-assisted 
fusion biopsy method to accurately target 18F-PSMA PET ROIs and to provide reliable data on 
18FPSMA PET diagnostic accuracy. We will develop an efficient and time-effective one-stop 
session 18F-PSMA PET/mpMRI examination for PCa diagnosis by using a fully hybrid PET/MRI. 
The simultaneous acquisition of PET using a new radiotracer such as 18F-PSMA and mpMRI 
provides metabolic structural and functional information regarding PCa status in a whole-body 
single session examination, thus representing an improvement and innovation for PCa staging. 
Data provided by this study will have potential clinical implications such as the improvement of 
csPCa detection and the reduction of clinically indolent PCa diagnosis, thus overdiagnosis and 
overtreatment. 
5.3. Assessment of Risks and Benefits ratio 
The prolonged acquisition time that characterizes fully hybrid PET/MRI is necessary to provide a 
one-stop-shop for the diagnosis of csPCa. Furthermore, PSMA PET, despite obviously entailing 
a low radiation exposure to patients, is a safe procedure already recommended for the 
characterization of PCa both in the staging and restaging phase by international guidelines (2). 
The low risk that this protocol entail is therefore justified by its potential clinical implications such 
as the improvement of csPCa detection and the reduction of clinically indolent PCa diagnosis, thus 
overdiagnosis and overtreatment. 
 
6. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Time point(s)  
Primary Objective 
To assess the accuracy and the 
predictive value of fully hybrid 
18F-PSMA PET/MRI for the 
diagnosis of csPCa  
Primary Endpoint 
Diagnostic accuracies of 18F-PSMA 
PET and mpMRI will be calculated by 
means of sensitivity: true positive/(true 
positive 
+ 
false 
negative) 
and 
specificity: true negative/(false positive 
+ true negative) using the prostate 
biopsy result as reference standard. 
PET/MRI 
examination 
at 
day 0, and biopsy 
at 
day 
1-30 
(within a month 
from 
imaging 
study) 
 
Secondary Objectives 
To compare the proportion of 
csPCa missed by 18F-PSMA 
PET scan or mpMRI alone  
Secondary Endpoints 
The proportion of csPCa (defined by 
analysis of prostate biopsy cores, ISUP 
grade equal or higher than 2) missed 
by PSMA PET scan or mpMRI alone 
will be calculated.  
 
PET/MRI 
examination 
at 
day 0, and biopsy 
at 
day 
1-30 
(within a month 
from 
imaging 
study) 
Exploratory Objectives 
To assess the proportion of 
unnecessary biopsies potentially 
spared  
Other 
Number of clinically insignificant PCa 
(ISUP grade 1) identified combining 
mpMRI and 18F-PSMA PET.  
PET/MRI 
examination 
at 
day 0, and biopsy 
at day 90 (+/-90) 

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7. EFFICACY AND SAFETY CRITERIA 
7.1. Efficacy Criteria 
Diagnostic accuracies of 18F-PSMA PET and mpMRI will be calculated by means of sensitivity: 
true positive/(true positive + false negative); specificity: true negative/(false positive + true 
negative); PPV: true positive/(true positive + false positive); and NPV: true negative/(true negative 
+ false negative) using the prostate biopsy result as reference standard 
7.2. Safety Criteria 
 
A large amount of evidence shows that 18F-PSMA is well tolerated, and it is not associated with 
serious adverse events (SAE) (6). Drug’s reaction could occur, in a very small percentage of the 
population as it is reported in the normal clinical practice. Patients presenting contraindication to 
PET/MRI examination will be excluded from the study a priori. More details on this can be found 
in the section “Exclusion criteria” of this protocol. 
 
8. TRIAL DESIGN 
In this single-arm phase II, prospective, monocentric study we will test whether addition of 18F-
PSMA PET scan to mpMRI helps improving the diagnostic pathway efficiency in identifying those 
men who should necessarily undergo TBx, because of high-risk to harbor csPCa. 
Furthermore, the combined use of 18F-PSMA PET and mpMRI for the diagnosis of PCa may also 
result in a reduced number of follow-up procedures in those patients who can safely avoid a 
prostate biopsy given the very low risk of harboring csPCa using a single, one-stop approach with 
both imaging modalities. A more efficient pre-biopsy triage test using the fully hybrid 18F-PSMA 
PET/MRI might result in the reduction of the total number of biopsies for men with a clinical 
suspicion of PCa, reducing also patient discomfort combining two different diagnostic procedures 
in one single step and avoiding, whenever possible, the biopsy-related side effects. 
 
A total of 167 consecutive patients with a clinical suspicion of csPCa (defined as the presence of 
PCa with ISUP grade equal or higher to 2), referred to simultaneous 18F-PSMA PET/MRI with 
mpMRI, will be identified and enrolled. PET/MRI images will be qualitatively and quantitatively 
evaluated by an experienced Nuclear Medicine and an experienced Radiologist physicians. In 
particular, for qualitative evaluation, lesions classified as PI-RADS higher or equal to 3 on mpMRI 
images and/or showing pathologically increased 18F-PSMA uptake on PET images, will be 
considered as positive for csPCa. All men will then receive a prostate biopsy (12-core random 
systematic prostate biopsy plus eventual targeted biopsy) as back-up histology according to the 
results of PET/MR imaging.  
 
Specifically, patients with both positive mpMRI and 18F-PSMA PET, defined as the presence of 
one or more lesions with PI-RADS higher or equal to 3 and an increased uptake of 18F-PSMA, 
will receive a 12-core random systematic prostate biopsy (TRUS-Bx) in addition to MRI targeted 
biopsy (MRI-TBx) and 18F-PSMA PET targeted biopsy (PSMA PETTBx). 

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Patients with both negative mpMRI and 18F-PSMA PET scan will receive a 12-core TRUS-Bx. 
Patients with only positive mpMRI will receive MRI-TBx and 12-core TRUSBx. Patients with only 
positive 18F-PSMA PET will receive 18FPSMA PET-TBx and 12-core TRUSBx. MRI-TBx will be 
performed by means of a fusion software-assisted approach using the Biojet system taking 4 cores 
in any mpMRI suspicious areas. PSMA PET-TBx will be performed taking 4 cores in the 
area of the prostate showing an increased tracer uptake. All prostate biopsy specimens will be 
evaluated by fully dedicated uro-pathologist.  
In order to calculate accuracy, sensitivity, specificity, positive predictive value and negative 
predictive value of 18F-PSMA PET/MRI for the identification of csPCa, 18F-PSMA PET/MRI 
findings will be correlated with histopathological samples gathered with prostate biopsy. 
The proportion of csPCa missed by PSMA PET scan or mpMRI alone will be then calculated. 
In order to study the proportion of unnecessary biopsies that could be spared by adding 18F-
PSMA PET to mpMRI in the triage phase, only patients with positive mpMRI and negative 18F-
PSMA PET scan will be considered for the analysis and the proportion of clinically insignificant 
PCa detected in this subset of patients will be assessed. In this way we will identify proportion of 
unnecessary prostate biopsies that could have been spared, thus reducing overdiagnosis. 
Furthermore, the potential role of quantitative PET and mpMRI parameters in identifying csPCa 
will be investigated. Specifically, recently emerging radiomic features will be evaluated, together 
with PET- and MRI-derived quantitative conventional imaging parameters, and regression 
analyses will be used for evaluating their role in predicting histopathological data. To assess the 
diagnostic performance of PET and MRI parameters, ROC curve analysis will be performed to 
select optimal cut-offs in predicting the presence of csPCa as defined by cytological examination 
and the corresponding diagnostic accuracy will be computed (more detailed information in the 
section “Statistics” of this protocol). No interim analyses are planned.  
 
The following measures will be taken in order to minimize the risk of bias: 
MpMRI is the standard of care diagnostic tool for staging and restaging in patients with Pca. The 
high expertise of the Center in prostate MRI has shown negligible inter-reader variability. All MRIs 
will be analysed by an experienced Radiologist (6 years of experience in prostate mpMRI). All 
PET exams will be analysed by an expert Nuclear Medicine physician (>10 years of experience in 
prostate PET). Furthermore, to avoid bias in the qualitative image anlaysis, PET and mpMR scans 
will be evaluated blind to the results of the other imaging modality. For efficacy analyses that 
require complete patient data, missing values during the treatment period will be replaced, for all 
variables, with the LOCF technique (Last Observation Carried Forward). Imputed values will be 
included in the analysis set(s), but will not change the original clinical database. For subjects who 
interrupt prematurely the trial due to the "adverse event", the BOCF technique (Basal Observation 
Carried Forward) will be used instead of the LOCF, in order to avoid the allocation of a positive 
result to patients to be considered treatment failures.  
 
8.1. Study duration  
Duration of enrollment: The enrolment will start on April 30th 2023 and will end before July 2025. 
Duration of treatment: PET/MRI examination takes about two hours. Then patients will undergo 
prostate biopsy (90 days +/- 90 days after imaging) 
Duration of total follow-up: A follow-up is not planned 
Duration of total trial period: Three years (36 months) 

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9. TRIAL POPULATION 
9.1. Trial Participants 
Participants with clinical suspicion of clinically significant prostate cancer (defined by ISUP grade 
equal or higher than 2) referred for simultaneous 18F-PET/MR, with mpMRI, examination.  
9.2. Inclusion Criteria 
1) Men at least 18 years of age referred with clinical suspicion of prostate cancer 
candidate for prostate biopsy 
2) Feasibility to undergo all procedures listed in protocol 
3) Ability to provide written informed consent 
 
9.3. Exclusion Criteria 
1) Prior treatment for prostate cancer 
2) Prior diagnosis of prostate cancer 
3) Contraindication to MRI (e.g. claustrophobia, pacemaker, estimated GFR lower or equal 
to 50mls/min) 
4) Contraindication to prostate biopsy 
5) Men in whom artifact would reduce the quality of the MRI (e.g. hip replacement) 
6) Unfeasibility to undergo any procedures listed in protocol 
 
9.4. Screening Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently entered in the study. Minimal information including demography, screening 
failure details, eligibility criteria, and any serious adverse event (SAE) experienced by the patients 
will be reported. 
 
10. TRIAL INTERVENTIONS  
10.1. 
Investigational Medicinal Product(s) (IMP) Description 
18F-PSMA synthesis is performed using an automatic synthesis module (NEPTIS) through the 
incorporation of 18F (produced by the IBA 18 MeV cyclotron) in a PSMA 1007 precursor molecule; 
after formulation and sterilization on a 0.22 um filter membrane, quality control is performed to 
evaluate the chemical, radiochemical, radionuclidic and microbiological purity of the final product 
in compliance with the monograph of Eu. Ph. 3116 
 
10.2. 
Treatment Schedule 
 
Experimental drug 
Dosage 
Route 
Day 
18F-PSMA 
Approximately  
4 MBq/Kg 
Intravenous 
0 

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10.3. 
Method for Assigning Subjects to Treatment Groups 
Not applicable 
10.4. 
Blinding of IMPs 
 
Not applicable 
 
10.5. 
Receiving and Storage of IMP 
Not applicable. The IMP is produced by the radio-pharmacy of Ospedale San Raffaele and used 
immediately due to its short half-life. 
 
10.6. 
Preparation, Administration and Accountability of the Trial Treatments 
Radiotracer synthesis: 18F-PSMA synthesis is performed using an automatic synthesis module 
(NEPTIS) through the incorporation of 18F (produced by the IBA 18 MeV cyclotron) in a PSMA 
1007 precursor molecule; after formulation and sterilization on a 0.22 um filter membrane, quality 
control is performed to evaluate the chemical, radiochemical, radionuclidic and microbiological 
purity of the final product in compliance with the monograph of Eu. Ph. 3116. 
PET/MR acquisition protocol: PET/MRI will start approximately 90 minutes after intravenous 
administration of 4 MBq/Kg of 18F-PSMA. A PET/MR total body acquisition and a high statistics 
pelvic PET simultaneously acquired to mpMRI will be performed. Using 3 Tesla PET/MR system 
the endorectal coil is not needed for the MR acquisition thus increasing patient compliance. 
MpMRI protocol will follow ESUR guidelines: axial T2 weighted sequence with large field of view 
(FOV), axial and sagittal T2 weighted sequence with small FOV, DWI sequence with small FOV 
b= 50, 800, 1400; 2000s/mm2 and ADC maps, T1-Lava Flex sequence of the pelvic region pre-
contrast and post-contrast, a high temporal resolution T1 perfusion sequence after IV injection of 
0.1 mmol/kg bolus of gadobutrol at a flow rate of 3.5 mL/s.  
PET/MRI qualitative analysis: images will be evaluated by expert Nuclear Medicine and 
Radiologist physicians blinded to each other on the Advantage Workstation (AW, General Electric 
Healthcare, Waukesha, WI, USA) where PET, MRI and fused PET/MRI images can be visualized 
in axial, coronal and sagittal planes. Focal uptake of 18F-PSMA higher than background and not 
associated with physiologic uptake was considered positive. For mpMRI, T2W morphological, 
diffusion (DWI) and perfusion (DCE) sequences will be used to define lesions according to 
PIRADS v. 2.1 classification (7). Lesions classified as PI-RADS >= 3 on mpMRI images and/or 
showing increased 18F-PSMA uptake on PET, will be considered positive for csPCa. 
Biopsy protocol: Each patient will receive a 12-core random systematic biopsy (TRUSBx) and 
mpMRI targeted biopsy as standard clinical procedure. MpMRI software assisted targeted biopsy 
will be performed using the BioJetTM fusion system (D&K Technologies, Barum, Germany) (8,9). 
Before biopsy both the prostate and each mpMRI suspicious lesion will be contoured and 
superimposed with the transrectal (TR) ultrasound image. TR ultrasound will be performed using 
a Flex Focus 500 machine with a biplanar transducer (BK Medical, Herlev, Denmark) (10). In 

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addition, 18F-PSMA PET targeted biopsy will be also performed, using the BioJetTM fusion 
system relying on PET images co-registered with mpMRI images for a correct contouring of both 
prostate and 18F-PSMA PET ROIs and superimposition with ultrasound images. Each mpMRI 
and 18F-PSMA PET ROI will be biopsied with a 4-cores targeted biopsy. Prostate biopsies will be 
carried out using a 18-gauge needle and a biopsy gun providing a specimen size of 18-22 mm. 
PET/MR quantitative analysis: ROIs on primary tumour showing 18F-PSMA uptake will be semi-
automatically defined on transaxial PET images and the following semi-quantitative parameters 
will be extracted: maximum standardised uptake value (SUVmax), mean SUV (SUVmean, using 
different thresholds and metabolic tumour volume (MTV) calculated at different thresholds. ROIs 
on the MR images, ADC and DCE maps will be drawn to measure MR parameters related to the 
lesions detected by MRI. 
Radiomic analysis: Volumes of interest (VOIs) will be manually segmented on 18F-PSMA PET, 
T2w-images and ADC maps by expert Nuclear Medicine and Radiologist physicians in 
correspondence of the intra-prostatic findings referable to the site of primary tumour. IBSI 
compliant radiomic features (11) will be extracted from VOIs and features reduction and selection 
procedures will be used to define a smaller set of radiomic features showing the best discrimination 
between csPCa and clinically insignificant PCa or healthy tissue. 
Remaining radio-pharmaceutical will be stored in a bunker at Ospedale San Raffaele and after 
radioactivity decay will be destroyed in accordance with the hospital and the applicable local, 
federal and national regulations. 
 
10.7. 
Compliance with Trial Treatment 
All patients that will complete PET/MRI examination and will undergo prostate biopsy will be 
considered compliant with the clinical trial. A through database containing all relevant information 
for this study will be generated and patients that fail to complete the study procedures will be 
annotated. PET/MRI acquisition protocol will be optimized to ensure, as much as possible, 
patients’ compliance. 
10.8. 
Concomitant Medication 
Only prior medication for PCa and concomitant medication that entail contraindication for PET/MR 
examination or biopsy will not be allowed, and therefore patients showing these characteristics 
will be excluded from the study (see section “Exclusion criteria”). 
10.9. 
Rescue Therapy 
Not applicable. 
10.10. 
Post-trial Treatment 
There will be not provision of the IMP beyond the rial period. 
 
10.11. 
Other Treatments (NIMPS: PeIMP - ReTNIMP) 
Not applicable. 
 

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10.12. 
Other Interventions 
Not applicable.

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11. TRIAL PROCEDURES 
 
 
Enrollment 
Screening 
Baseline 
Study Visit 
Final Study 
Visit 
Procedures 
Day 
-20 
(+/- 20 days) 
-20  
(+/- 20 days) 
0 
(+/- 0 days) 
+90 
(+/-90 days) 
+90 
(+/-90) 
Informed consent 
x 
 
 
 
 
Demographics 
 
x 
 
 
 
Medical history 
 
x 
 
 
 
Eligibility assessment 
 
x 
 
 
 
Urological visit, including 
physical examination 
 
x 
 
 
 
Performance status  
 
x 
 
 
 
Study drug administration 
 
 
x 
 
 
Compliance evaluation 
 
 
x 
 
 
Radiologic/Imaging 
assessment 
 
 
x 
 
 
Prostate biopsy 
 
 
 
x 
 
Adverse event assessments 
 
x 
x 
x 
x 

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11.1. 
Informed Consent 
Consent forms describing in detail the study procedures, and risks, are given to the participant 
and written documentation of informed consent is required prior to starting to administer 18F-
PSMA. The following consent materials are submitted with this protocol “Consenso informato 
v2.0”. 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be EC-
approved, and the participant will be asked to read and review the document. The investigator 
(according to applicable regulatory requirements) or a person designated by the investigator, and 
under the investigator's responsibility, will explain the research study to the participant and answer 
any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to 
participate. The participant MUST signed the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. A copy of the informed 
consent document will be given to the participants for their records. The informed consent process 
will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare of 
the participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
11.2. 
Subject Recruitment and Screening  
 
A total of 167 consecutive patients with a clinical suspicion of csPCa (defined as the presence of 
PCa with ISUP grade equal or higher to 2), referred to simultaneous 18F-PSMA PET/MRI with 
mpMRI, will be identified and enrolled. The sample size was computed based on sensitivity 
analysis for the detection of clinically significant PCa. Assuming an average prevalence of clinically 
significant PCa of 56%, a total sample size of 167 patients is sufficient for evaluating a sensitivity 
of 96% with an absolute precision of 4% (at 95% confident level). Patients will be identified and 
enrolled by the department of Urology at OSR following standard procedures for the evaluation of 
suspected csPCa, including prostate specific antigen (PSA) examination. 
 
11.3. 
Subject Identification 
 
Starting from the signature of the informed consent by the patient or patient’s legal tutor, the 
subjects is considered enrolled in the clinical trial.  

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A subject identification code will be assigned consecutively (i.e.: csPCa_XXX; where csPCa is the 
abbreviation of the acronym, XXX is the progressive subject number in increasing order starting 
from 001). 
A patient identification list will be kept. 
 
11.4. 
Randomization and Blinding 
Not applicable. 
11.5. 
Baseline Assessments 
At the screening visit the urologist will evaluate the risk of csPCa, according to the normal clinical 
practice.  
 
11.6. 
Visits and Follow Up 
The protocol does not include a follow-up. At Day 0 patients undergo 18F-PSMA PET/MRI 
examination. Then patients undergo prostate biopsy. Analysis of prostate biopsy cores is 
necessary to validate imaging findings and to diagnose csPCa. No further time points are 
considered.  The patients will then continue to be monitored according to the normal clinical 
practice regardless of their participation in this study. 
 
 
11.7. 
Definition of End of Study 
According to the study design, the end of the study is defined as the date on which the last patient 
completes the last visit (Day 90 ± 90 days).  
 
11.8. 
Premature termination or suspension of a trial 
This study may be temporarily suspended or prematurely terminated by the PI if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to funding agency and 
regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly 
inform study participants, the EC and will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and informed of the closure of the study 
Circumstances that may warrant termination  include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, EC, and/or Competent Authority. 
In terminating the study, the Sponsor and the Principal Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 

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12. DISCONTINUATION AND WITHDRAWAL 
Participants can withdraw from the study at any time. Patients that decide to withdraw from the 
study will undergo mpMRI, as for clinical practice, before prostate biopsy. 
12.1. 
Discontinuation of Trial Intervention 
Patients can decide to withdraw from PET/MRI examination at any time. Patients that decide to 
discontinue from study intervention will be treated according to the normal clinical practice. 
However, data of patients that did not complete the PET/MR intervention will be discarded from 
the analyses. 
12.2. 
Participant Discontinuation/Withdrawal from the Trial 
 
Participants can withdraw from the study at any time upon request. In addition, the Investigator 
may discontinue or withdrawal a participant from the trial for the following reason: 
• 
Significant protocol deviation 
• 
Significant non-compliance with treatment regimen or trial requirements 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
clinical records and in Case Report Form (CRF). Subjects who sign the informed consent form but 
do not perform 18F-PSMA PET/MRI examination may be replaced. Subjects who sign the 
informed consent form and performed 18F-PSMA PET/MRI examination, and subsequently 
withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
12.3. 
Lost to Follow-Up 
The protocol does not include a follow-up. At Day 0 patients undergo 18F-PSMA PET/MRI 
examination. Then patients undergo prostate biopsy. Analysis of prostate biopsy cores is 
necessary to validate imaging findings and to diagnose csPCa. No further time points are 
considered.   
13. SAMPLE HANDLING 
Not applicable. 
  
14. PATIENT SAFETY 
 
adverse events (AE) will be recorded by a member of the research team or clinical team on an AE 
report form. All serious AE (SAE) will be recorded on a SAE report form. Both AE and SAE should 
be recorded in the medical notes. 
 

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14.1. 
Safety profile of the IMP 
The known side effects for the IMP are reported with the relative frequencies. The safety profile of 
the IMP is based on the Summary of Product Characteristics and/or IB are reported below. 
 
14.2. 
Adverse Event Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered, a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An adverse event (AE) can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product. Reference: GCP ICH E6(R2) 
Adverse Drug Reaction (ADR) 
 
In the pre-approval clinical experience with a new medicinal product or its new 
usages, particularly as the therapeutic dose(s) may not be established: all 
noxious and unintended responses to a medicinal product related to any dose 
should be considered adverse drug reactions. The phrase responses to a 
medicinal product means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. 
Regarding marketed medicinal products: a response to a drug which is noxious 
and unintended, and which occurs at doses normally used in man for prophylaxis, 
diagnosis, or therapy of diseases or for modification of physiological function. 
Reference: GCP ICH E6(R2) 
Serious Adverse Event (SAE) 
or Serious Adverse Drug 
Reaction (Serious ADR) 
Any untoward medical occurrence that at any dose: 
– results in death, 
– is life-threatening, 
– requires inpatient hospitalization or prolongation of existing hospitalization, 
– results in persistent or significant disability/incapacity, 
or 
– is a congenital anomaly/birth defect. 
Reference: GCP ICH E6(R2) 
Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended. 
‘‘Unexpected,’’ as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug 
but are not specifically mentioned as occurring with the particular drug under 
investigation. 
CFR Title 21 
 
 
 
14.3. 
Adverse Event Severity Grading Scale 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; no intervention indicated 

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Grade 2 
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
 (ADL) 
Grade 3 
Severe  
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care ADL 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death 
Death related to AE 
Reference: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
 
14.4. 
AE Attribution Scale  
RELATIONSHIP 
ATTRIBUTION 
DESCRIPTION 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the intervention.  
Unlikely 
The AE is doubtfully related to the intervention. 
Related to 
investigational 
agent/intervention 
Possible 
The AE may be related to the intervention. 
Probable 
The AE is likely related to the intervention.  
Definite 
The AE is clearly related to the intervention. 
Reference: NCI Guidelines: Adverse Event Reporting Requirements 
 
14.5. 
Procedures for Reporting Adverse Events  
All AEs occurring during the safety window for the trial as defined above that are observed by the 
Investigator or reported by the participant will be reported in the trial CRF. 
The following information will be reported in the CRF: description, date of onset and end date, 
severity, assessment of relatedness to trial medication, other suspect drug or device and action 
taken.  Follow-up information should be provided as necessary. 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe. 
Non-serious AEs considered related to the trial medication as judged by a medically qualified 
investigator will be followed up either until resolution or until the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient 
severity to require the participant’s removal from treatment. A participant may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE.  If either of these 
occurs, the participant must undergo an end of trial assessment and be given appropriate care 
under medical supervision until symptoms cease, or the condition becomes stable.  
14.6. 
Reporting Procedures for Serious Adverse Events 

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All SAEs, defined as serious using the MedDRA (Medical Dictionary for Regulatory Activities) 
terms, will be reported. Using the SAE Reporting Form, the PI must communicate the SAEs to the 
OSR Clinical Trial Pharmacy (farmacia.trialsclinici@hsr.it) within 24 hours of becoming aware of 
the event. 
All deaths that occur during the course of the study must always be reported to the ethics 
committee. 
14.7. 
Follow-up of AE / SAE / ADR 
The Investigator should take all appropriate measures to ensure the safety of the patients. 
Notably, they should follow up on the outcome of any event (clinical signs, laboratory values, etc.) 
until resolution or until the event is considered stable. 
In the case of any Serious Adverse Event or Serious Adverse Drug Reaction, the patient must 
be followed up until clinical recovery is complete and laboratory results have returned to normal, 
or until progression has been stabilized. This may imply that follow-up will continue after the 
patient has left the study and that the Ethics Committee may request additional investigations. 
 
14.8. 
SUSAR Reporting 
SUSARs related to the IMP(s) or PeIMP(s) will be reported by the PI to the OSR Clinical Trial 
Pharmacy (farmacia.trialsclinici@hsr.it), within 24 hours of becoming aware of the event, using 
the CIOMS (Council for International Organizations of Medical Sciences) form. 
Subsequently, the Clinical Trial Pharmacy will report the SUSARs to the relevant Competent 
Authority (via Eudravigilance) and the EC. For fatal and life-threatening SUSARS, the Pharmacy 
must report the SUSAR within 7 calendar days. Any additional relevant information will be reported 
within 8 calendar days of the initial report. All other SUSARs will be reported within 15 calendar 
days. 
Treatment codes will be un-blinded for specific participants.  
Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the 
same Sponsor, whether or not the event occurred in the current trial. 
 
14.9. 
Development Safety Update Reports 
As part of the annual report and in accordance with IOG 226 “Farmacovigilanza negli studi clinici 
interventistici farmacologici no-profit promossi da OSR”, the PI will prepare the DSUR in 
collaboration with the Clinical Trial Pharmacy.  
14.10. 
Unblinding Procedures 
Not applicable 
15. DATA MANAGEMENT   
15.1. 
Definition of source data and source documents  
Source Data: All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or certified 

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copies). Any data recorded directly on the CRFs (i.e., no prior written or electronic record of data), 
is considered to be source data. 
Source Documents: Original documents, data, and records (e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subjects' diaries or evaluation checklists; pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions certified 
after verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, or records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial). 
All parameters asked for in the case report form (CRF) should be documented in the source 
documents. 
 
A record of patient screen failures will be maintained for patients who do not qualify for enrollment, 
including the reason for the screen failure. 
15.2. 
Documentation of data Case Report Forms (CRFs)  
All relevant data collected during the study for all of the patients enrolled in the study shall be 
entered in the CRF by the responsible investigator or someone authorized by the investigator in a 
timely manner (as soon as possible after the information is collected) to ensure that they are clear 
and legible. The physician shall confirm the completeness, correctness, plausibility, and 
compliance with the ICH guidelines and the institutional SOPs of the data by dated signature. An 
explanation must be provided for any and all missing data. The entries shall be made with black 
ballpoint pen. 
The properly filled in CRF will remain in the trial site; in case of electronic CRF, a copy of all pages 
will be conserved in the trial site. 
15.3. 
Data Recording and Record Keeping 
The investigator shall arrange for the retention of Essential Documents for the Conduct of a Clinical 
Trial (according to Chapter 8 of GCP ICH E6(R2) (e.g., patient files, other source data, and the 
Trial Master File) for at least 25 years after the completion or discontinuation of the study. 
 
15.4. 
Data Protection  
The researcher will have to keep the patient's original data and a copy of the signed written 
informed consent. The files will be kept in a locked closet in Nuclear Medicine Unit. 
 
16. STATISTICS 
16.1. 
Description of Statistical Methods 
Diagnostic accuracies of 18F-PSMA PET and mpMRI will be calculated by means of sensitivity: 
true positive/(true positive + false negative); specificity: true negative/(false positive + true 
negative); PPV: true positive/(true positive + false positive); 
and NPV: true negative/(true negative + false negative) using the prostate biopsy result as 
reference standard. 

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- The assessment of quantitative imaging parameters, including radiomic features and 
conventional parameters, characterizing regions of csPCa will be performed by generalized Linear 
Mixed Models for binary responses. Logistic regression will be used for evaluating PET and MRI 
parameters and texture features in predicting the presence of csPCa, as defined by biopsy results. 
To assess the diagnostic performance of PET and MRI parameters, ROC curve analysis will be 
performed to select optimal cut-offs in predicting the presence of csPCa, as defined by cytological 
examination, and the corresponding diagnostic accuracy values will be computed. 
- McNemar test will be used to compare the proportion of csPCa missed by 18F-PSMA PET or 
mpMRI alone (12). 
- All statistical analyses and data processing will be performed using the R statistical package or 
the SPSS software. All p-value will be rounded to three decimal places. Statistical significance will 
be declared if the rounded p-value will be less than 0.050. Two-sided 95% confidence intervals 
will be calculated. 
16.2. 
Sample Size Determination 
The sample size was computed based on sensitivity analysis for the detection of clinically 
significant PCa. Assuming an average prevalence of clinically significant PCa of 56%, a total 
sample size of 167 patients is sufficient for evaluating a sensitivity of 96% with an absolute 
precision of 4% (at 95% confident level). 
16.3. 
Analysis Populations  
Participants with clinical suspicion of clinically significant prostate cancer (defined by ISUP grade 
equal or higher than 2) referred for simultaneous 18F-PET/MR, with mpMRI, examination. 
16.4. 
Interim Analysis  
No interim analyses are planned. 
16.5. 
Stopping Rules 
Not applicable.  
17. ETHICAL AND REGULATORY CONSIDERATIONS 
This clinical trial will be conducted in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments established by the World 
Medical Assemblies, and the ICH guidelines for Good Clinical Practice.  
This clinical trial will be conducted in compliance with all international laws and regulations; 
national laws and regulations of the country in which the clinical trial is performed; as well as any 
other applicable guidelines. 
 
17.1. 
Responsibilities of the Investigator(s) 
The Investigator(s) undertake(s) the responsibility to perform the study in accordance with this 
Protocol, Good Clinical Practice, and the applicable regulatory requirements. The Investigator is 
required to ensure compliance with the investigational product schedule, visits schedule, and 
procedures required by the protocol. The Investigator agrees to provide all information requested 
in the Case Report Form (CRF) in an accurate and legible manner. The investigator may 

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implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to 
trial subjects without prior EC approval/favorable opinion. As soon as possible, the implemented 
deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted. The investigator must have available an adequate number of qualified staff 
and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely. 
 
17.2. 
Ethics Committee (EC) Approvals  
This clinical trial protocol as well as the Informed Consent are to be submitted to the appropriate 
Ethics Committee, and it is mandatory to obtain the written and dated approval, signed by the 
chairman with Ethics Committee(s) composition. 
The clinical trial the documents reviewed, the list of voting members and their qualifications, and 
the date of the review should be clearly stated on the written Ethics Committee approval. 
 
17.3. 
Other Ethical Considerations 
There are no additional ethical considerations to be made. 
 
18. QUALITY ASSURANCE AND QUALITY CONTROL 
The trial will be conducted in accordance with the current approved protocol, GCP, relevant 
regulations, and standard operating procedures. A risk assessment and monitoring plan will be 
prepared before the study opens and will be reviewed as necessary over the course of the trial to 
reflect significant changes to the protocol or outcomes of monitoring activities. Investigators 
involved in the study will permit study-related monitoring, audits, EC review, and regulatory 
inspections by providing direct access to all study records.  
The Investigator should notify the CTC promptly of any inspection scheduled by any regulatory 
authorities and will promptly forward copies of any inspection reports received. 
18.1. 
Monitoring  
Regular monitoring will be performed, according to the Monitoring Plan. Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents. Following written 
standard operating procedures, the monitors will verify that the clinical trial is conducted, and data 
are generated, documented, and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements. 
18.2. 
Deviation from study protocol 
A deviation from the protocol is an unintended departure from the procedures or processes 
approved by the Sponsor and the EC.  
The Investigator or designee must document and explain in the patient’s source documentation 
any deviation from the approved protocol. The Investigator may implement a deviation from the 
protocol to eliminate an immediate hazard to study patients without prior IEC approval. As soon 
as possible after such an occurrence, the implemented deviation, the reasons for it, and any 
proposed protocol amendments should be submitted to the EC for review and approval, and to 
the regulatory authorities, if required.  

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Protocol deviations will be documented by the clinical monitor throughout the course of monitoring 
visits. Investigators will be notified in writing by the monitor of deviations. As required by local 
regulatory authorities, the Investigator will notify the EC of any applicable protocol deviations in a 
timely manner. 
Every deviation from the trial protocol must be specified and documented separately for each 
patient. The investigator must consult with the monitor and discuss the type and extent of deviation 
as well as the possible consequences for further participation of the patient in the study. If the 
evaluability of a patient is questionable, the coordinating investigator will be consulted. 
 
18.3. 
Data and Safety Monitoring Board 
Not applicable. 
 
18.4. 
DSMB roles and responsibilities 
Not applicable. 
 
19. FINANCE AND INSURANCE 
 
19.1. 
Funding 
The Italian Ministry of Health funded this study with 450000 euros. Please, refer to the project 
“bando ricerca finalizzata, number: RF-2021-12372278, page: 25” attached to this protocol for detailed 
information regarding funding. 
 
19.2. 
Patient Insurance 
We note that an insurance coverage, which guarantees any damage to the person deriving from 
the experimentation, according to the indications provided by the Ministerial Decree of Health 14 
July 2009, will be activated for the entire duration of the trial. Please, refer to the attached 
document “Patient insurance” for details. 
19.3. 
Contractual arrangements  
Not applicable. 
  
20. END OF CLINICAL TRIAL 
In accordance with applicable regulation, ICH GCP and SOPs, the PI shall notify the end of the 
clinical trial within 15 days from the end of the clinical trial.  
The PI shall notify a temporary halt of a clinical trial for reasons not affecting the benefit-risk 
balance within 15 days from the temporary halt of the clinical trial and shall include the reasons 
for such action. When a temporarily halted clinical trial is resumed the PI shall notify within 15 days 
from the restart of the temporarily halted clinical trial. If a temporarily halted clinical trial is not 

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resumed within two years, the expiry date of this period or the date of the decision of the PI not to 
resume the clinical trial shall be deemed to be the date of the end of the clinical trial. In the case 
of early termination of the clinical trial, the date of the early termination shall be deemed to be the 
date of the end of the clinical trial. In the case of early termination of the clinical trial for reasons 
not affecting the benefit-risk balance, the PI shall notify the reasons for such action and, when 
appropriate, follow-up measures for the subjects. 
 
Upon completion or termination of the study, the study monitor will conduct site closure activities 
with the Investigator or site staff (as appropriate). 
20.1. 
SUMMARY OF THE RESULTS OF THE CLINICAL TRIAL 
Irrespective of the outcome of a clinical trial, within one year from the end of a clinical trial, the PI 
shall submit a summary of the results of the clinical trial. The content of that summary is set out 
according to Annex IV of the EU regulation N° 536/2014. It shall be accompanied by a summary 
written in a manner that is understandable to laypersons. The content of that summary is set out 
in according to Annex V of the EU regulation N° 536/2014. 
 
21. INTELLECTUAL PROPERTY  
Not applicable. 
 
22. PUBLICATION POLICY 
Due to the high relevance and originality of the proposed project, the planned and developed 
methodology, together with the obtained results, will be objective of scientific dissemination 
(scientific paper in peer reviewed journals and/or presentation at medical conferences) for the 
scientific community in the field of Imaging, and particularly PET/MR imaging, in the field of 
radiomics and Urology.  
 
 
23. REFERENCES 
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T.H. van der Kwast TBL, M.D. Mason, S. O’Hanlon, D.E. Oprea-Lager GP, H.G. van der 
Poel, O. Rouvière, I.G. Schoots. D. Tilki, T. Wiegel, T. Van den Broeck MC, A. Farolfi, N. 
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24. APPENDIX A:  AMENDMENT HISTORY 
Not applicable. 
 
25. APPENDIX B:  LIST OF CLINICAL SERVICES / LABORATORIES 
Not applicable.