Optimization of Prostate Biopsy - Micro-Ultrasound Versus MRI: A 3-arm Randomized Controlled Trial Evaluating the Role of 29MHz Micro-ultrasound in Guiding Prostate Biopsy in Men With Clinical Suspicion of Prostate Cancer.
Phase: NA
Conditions: Prostate Cancer
Sponsor: Sunnybrook Health Sciences Centre

 
 
 
Clinical Investigation Plan and Study Protocol for  
Optimization of Prostate Biopsy - Micro-Ultrasound versus MRI (OPTIMUM): A 3-arm 
randomized controlled trial evaluating the role of 29MHz micro-ultrasound in guiding 
prostate biopsy in men with clinical suspicion of prostate cancer 
 (EVU-2021-001) 
 
NCT05220501 
 
 
 
Revision: 
1.5 
Status: 
Approved 
Release Date: 
July 26, 2023 
 
 
 
 

CIP and Study Protocol for EVU-2021-001 
 
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Revision History 
 
Date 
Author 
Rev 
Description of Change 
28 July 2021 
B. Wodlinger 
1.0 
Initial revision  
4 Aug 2021 
B. Wodlinger 
1.1 
Updated per internal feedback for alignment with 
ISO14155:2020 
11 Aug 2021 
B. Wodlinger 
1.2 
Updated per internal feedback 
8 May 2023 
B. Wodlinger 
A. Matte 
1.2.1 
Minor update to remove requirement for individual 
sites to insert site specific information in the 
protocol as this information is already included in 
the CTAs with each site (5.3.3, 5.4.1).  New version 
references location of this information.   
Wording around study sponsor clarified (1.0, 5.1, 
5.3.2) 
5.4.6  Clarified patient follow-up survey completed 
7-days post biopsy 
5.8.1.1 Updated schema figure to correct typo in 
arm numbers  
5.8.3.1  Updated inclusion criterion to clarify prior 
MRI status (for consistency with blinding in protocol) 
5.8.6  Optional Biopsy note taking form added as 
source document for sites requiring a paper record 
during biopsy procedure 
5.11  Amendment to CIP has been clarified to 
require only agreement with Study PI not each site 
PI 
19 July 2023 
B. Wodlinger 
A. Matte 
 
1.5 
5.9.6  Duplicate entry removed 
Versions 1.3,1.4 skipped to ensure all sites have 
later version dates for ethics submission 
 
 

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Table of Contents 
 
1 
Purpose ...................................................................................................................... 5 
2 
Scope ........................................................................................................................ 5 
3 
Definitions .................................................................................................................. 5 
4 
References ................................................................................................................. 7 
5 
Clinical Investigation Infrastructure ............................................................................... 8 
5.1 
Responsibilities ...................................................................................................... 8 
5.2 
Contents of the CIP ................................................................................................ 8 
5.3 
General information ............................................................................................... 8 
5.3.1 
Identification of the CIP .................................................................................... 8 
5.3.2 
Identification of the sponsor .............................................................................. 9 
5.3.3 
Identification of the investigators ....................................................................... 9 
5.3.4 
Overview of the investigational protocol ............................................................. 9 
5.4 
Device Description ............................................................................................... 10 
5.4.1 
Device Identification ...................................................................................... 11 
5.4.2 
Purpose of the device in the context of the investigation ..................................... 11 
5.4.3 
Materials that contact the patient .................................................................... 11 
5.4.4 
Instructions for use ........................................................................................ 12 
5.4.5 
Training requirements .................................................................................... 12 
5.4.6 
Medical procedures ........................................................................................ 12 
5.5 
Justification for the Design .................................................................................... 13 
5.5.1 
Evaluation of pre-clinical data.......................................................................... 14 
5.5.2 
Clinical evaluation .......................................................................................... 14 
5.6 
Risks and Benefits................................................................................................ 16 
5.6.1 
Device risk analysis and management .............................................................. 16 
5.6.2 
Risks associated with participation in the clinical investigation ............................. 16 
5.6.3 
Possible interactions with concomitant medical treatments .................................. 17 
5.7 
Objectives and Hypothesis .................................................................................... 17 
5.7.1 
Objectives .................................................................................................... 17 
5.7.2 
Hypothesis .................................................................................................... 17 
5.7.3 
Claims .......................................................................................................... 18 
5.7.4 
Risks ............................................................................................................ 18 
5.8 
Design of the Clinical Investigation ........................................................................ 19 
5.8.1 
General ........................................................................................................ 19 
5.8.2 
Medical devices and comparators ..................................................................... 20 
5.8.3 
Subjects ....................................................................................................... 20 
5.8.4 
Procedures .................................................................................................... 22 
5.8.5 
Monitoring Plan ............................................................................................. 22 
5.8.6 
Case Report Forms ........................................................................................ 25 
5.8.7 
Identity of study subjects ............................................................................... 25 
5.9 
Statistical considerations ...................................................................................... 25 
5.9.1 
Statistical design, method and analytical procedures .......................................... 25 
5.9.2 
Sample size .................................................................................................. 26 
5.9.3 
Level of significance and power of the clinical investigation ................................. 26 
5.9.4 
Expected drop-out rates ................................................................................. 26 
5.9.5 
Pass/fail criteria ............................................................................................. 26 
5.9.6 
Provision for an interim analysis ...................................................................... 26 
5.9.6 
Criteria for the termination of the clinical investigation ....................................... 27 
5.9.7 
Procedures for reporting deviation from the statistical plan ................................. 27 
5.9.8 
Specification of subgroups for analysis ............................................................. 27 
5.9.9 
Procedures that take into account all data ......................................................... 27 
5.9.10 
Treatment of missing, unused data ............................................................... 27 

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5.9.11 
Exclusion of data ........................................................................................ 28 
5.9.12 
Subjects at multi-center investigations .......................................................... 28 
5.10 
Data Management............................................................................................. 28 
5.10.1 
Data review ............................................................................................... 28 
5.10.2 
Data verification and validation .................................................................... 28 
5.10.3 
Data retention ............................................................................................ 28 
5.10.4 
Clinical quality assurance ............................................................................. 29 
5.11 
Amendments to the CIP ..................................................................................... 29 
5.12 
Deviations from the CIP ..................................................................................... 29 
5.13 
Device Accountability ........................................................................................ 29 
5.14 
Statements of Compliance ................................................................................. 30 
5.15 
Informed Consent Process ................................................................................. 30 
5.16 
Adverse Events, Adverse device effects, and device deficiencies ............................. 30 
5.16.1 
Reporting adverse events ............................................................................ 30 
5.16.2 
Device deficiency reporting process .............................................................. 31 
5.16.3 
Foreseeable adverse events ......................................................................... 31 
5.17 
Vulnerable population ........................................................................................ 31 
5.18 
Suspension or premature termination of the clinical investigation ........................... 31 
5.19 
Publication policy .............................................................................................. 32 
5.20 
Critical Literature Review ................................................................................... 32 
5.21 
Bibliography ..................................................................................................... 37 
 
List of Appendices 
 
Appendix A 
Sponsor Responsibilities .............................................................................. 40 

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1 Purpose 
The purpose of this Clinical Investigation Plan and Study Protocol (CIP) is to present information 
for the OPTIMUM clinical investigation, including the scientific basis for the study, the procedural 
details, the ExactVu High Resolution Micro-Ultrasound System (referred to in this document as 
ExactVu), its safety details, and administrative details.  
 
The CIP was developed by a scientific panel organized by Exact Imaging and led by Dr. Lawrence 
Klotz who is acting as the overall study principal investigator and sponsor and has been designed 
in such a way as to optimize the scientific validity and reproducibility of the results of the study in 
accordance with current clinical knowledge and practice so as to fulfill the objectives of the 
investigation. 
 
2 Scope 
This CIP and the investigation itself are designed to meet applicable requirements and regulations 
of Health Canada, Europe and US FDA for conducting clinical investigations.  The contents of the 
CIP follow the requirements identified in ISO 14155 Clinical investigation of medical devices for 
human subjects.  
 
The investigation is a non-significant risk (NSR) investigation.  ExactVu is cleared for sale in the 
United States (Class II), Europe (Class IIa), Canada (Class III), and Israel (Class IIa). 
 
This plan is also intended to serve as the Investigator’s Brochure for the purposes of this 
investigation.  It also serves as the Study Protocol for the purposes of this investigation and 
provides the procedure details for the biopsy and pathology analysis. 
 
3 Definitions 
Term 
Definition 
Adverse 
Device Effect 
Adverse event related to the use of an investigational medical device 
 
NOTE 1 This definition includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device. 
 
NOTE 2 This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device. 
Adverse Event 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the investigational medical 
device 
 
NOTE 1 This definition includes events related to the investigational medical 
device or the comparator. 
 
NOTE 2 This definition includes events related to the procedures involved. 
 

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Term 
Definition 
NOTE 3 For users or other persons, this definition is restricted to events 
related to investigational medical devices. 
Case Report 
Form 
Document designed to record all information to be reported to the Sponsor on 
each subject as required by the CIP 
 
Clinical 
Investigation 
Plan and 
Study Protocol 
(referred to as 
“CIP”) 
A document that states the rationale, objectives, design, medical procedures 
and proposed analyses, methodology, conduct and record keeping of the 
clinical investigation. 
 
The Clinical Investigation Plan and Study Protocol is designed in such a way as 
to optimize the scientific validity and reproducibility of the results of the study 
in accordance with current clinical knowledge and practice so as to fulfill the 
objectives of the investigation in determining the safety and performance of a 
device, including undesirable side effects. 
Clinical 
Investigator’s 
Brochure 
A compilation of the clinical and nonclinical data on the investigational product 
which is relevant to the study of the investigational product in human subjects.
 
Its purpose is to provide the investigators and others involved in the 
investigation with the information to facilitate their understanding of the 
rationale for, and their compliance with key features of the CIP. The Clinical 
Investigator’s Brochure also provides insight to support the clinical 
management of the study subjects during the course of the clinical 
investigation.   
Clinically 
significant 
cancer 
Clinically significant prostate cancer for the purposes of this study is defined as 
tumors where Gleason score > 6, or ISUP grade > 1. 
 
Clinically insignificant cancer is defined as Gleason score = 6 or ISUP = 1. 
Comparator 
A medical device, therapy (e.g. active control), placebo or no treatment, used 
in the reference group in a clinical investigation 
Declaration of 
Helsinki 
A statement of ethical principles for medical research involving human 
subjects, including research on identifiable human material and data.  The 
Declaration of Helsinki was developed by the World Medical Association. 
 
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant 
paragraphs. 
Device 
Deficiencies 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance 
 
NOTE Device deficiencies include malfunctions, use errors, and inadequate 
labeling. 
ROC curve  
Receiver operating characteristic curve, a graphical plot used in statistical 
analysis is created by plotting the true positive rate (TPR) against the false 
positive rate (FPR) 
Study Monitor 
Individual responsible for assessing the investigator's compliance with the CIP 
and for performing source-data verification. 
 
The monitor shall have access to the source documents and other information 
needed to ensure investigator compliance with the CIP and applicable rules 
and regulations, and to assess the progress of the clinical investigation. 
 

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Term 
Definition 
NOTE The monitor is also responsible for reporting on the progress of the 
clinical investigation, including the compliance of the investigators. 
Serious 
adverse 
device effect 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event 
Serious 
adverse event 
Adverse event that 
a) led to death 
b) led to serious deterioration in the health of the subject, that either resulted 
in 
1) a life-threatening illness or injury 
2) a permanent impairment of a body structure or a body function 
3) in-patient or prolonged hospitalization 
4) medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function 
5) chronic disease 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
NOTE Planned hospitalization for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not considered a 
serious adverse event. 
Sponsor 
Individual or organization who or which takes responsibility for the initiation 
and/or implementation of a clinical investigation 
TRUS 
Transrectal Ultrasound 
 
micro-US refers to transrectal ultrasound procedures performed using a high-
frequency transducer 
 
Unanticipated 
serious 
adverse 
device effect 
Serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis 
report 
 
NOTE Anticipated serious adverse device effect (ASADE) is an effect which by 
its nature, incidence, severity or outcome has been identified in the risk 
analysis report. 
 
4 References 
1. ISO 14155:2020  Clinical investigation of medical devices for human subjects – Good 
clinical practice 
2. Council Directive 93/42/EEC (as amended by 07/47/EC) (the “Medical Devices Directive”) 
3. EU Medical Device Regulations (MDR) 2017/745  
4. MDCG 2021-6 Regulation (EU) 2017/745 (April 2021) – Questions & Answers regarding 
clinical investigation 
5. MDCG 2021-08 (May 2021) Clinical investigation application/notification documents 
6. MDCG 2021-20 (July 2021) Instructions for generating CIV-ID for MDR Clinical 
Investigations 

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7. EN ISO 13485:2016 Medical Devices - Quality Management Systems – Requirements for 
regulatory purposes 
8. 21 CFR Part 812 Subpart B – Investigational Device Exemptions 
9. Guidance for Industry and FDA Staff - Information for Manufacturers Seeking Marketing 
Clearance of Diagnostic Ultrasound Systems and Transducers 
10. ISO 14971:2019 Medical devices – Application of risk management to medical devices 
11. Clinical Trials.gov, U.S. National Library of Medicine 
12. Canadian Medical Device Regulations, Good and Drug Act, SOR/98-282 
13. Health Canada Guidance Document, Applications for Medical Device Investigational Testing 
Authorizations Effective Date 208/10/01 
5 Clinical Investigation Infrastructure  
5.1 Responsibilities 
All parties involved in the conduct of the clinical investigation shall share the responsibility for its 
ethical conduct in accordance with their respective roles in the clinical investigation. 
 
The investigation will be conducted by a consortium of investigators from 12-20 international 
institutions in Canada, the United States, and Europe.   
 
Exact Imaging, as well as the study principal investigator/study sponsor (Dr. Laurence Klotz), and 
each site principal investigator shall agree to the CIP and any amendments and indicate their 
approval and agreement by signing and dating the signature page of this CIP. 
5.2 Contents of the CIP 
The CIP includes the information about the topics identified in the following sections.  If the 
required information is written in other documentation related to the investigation, for example 
consent forms or case report forms, such documentation shall be referenced in this CIP, and 
controlled according to Exact Imaging’s standard operating procedures. 
 
Applicable documents shall be included with this CIP in regulatory submissions as required, and 
any other referenced documents shall be made available on request to each institution or its 
reviewing research ethics board (IRB/REB). 
 
5.3 General information 
5.3.1 Identification of the CIP 
The title for the clinical investigation is Optimization of Prostate Biopsy - Micro-Ultrasound versus 
MRI (OPTIMUM): A 3-arm randomized controlled trial evaluating the role of 29MHz micro-ultrasound 
in guiding prostate biopsy in men with clinical suspicion of prostate cancer.  
 
The revision number and date of the document are indicated in the Revision History.  The Exact 
Imaging identifier for the investigation is EVU-2021-001. 

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5.3.2 Identification of the sponsor 
This is an investigator-initiated trial, which is organized by a consortium of Principal Investigators 
led by the lead study site investigator and study sponsor: 
 
Dr. Laurence H. Klotz  
Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto  
2075 Bayview Ave. #MG408, Toronto, ON  
M4N 3M5  
Canada 
 
Laurence.klotz@sunnybrook.ca 
Phone: 416-480-4673 
Fax: 416-480-6121 
 
Exact Imaging Inc. is the manufacturer of the ExactVu Micro-Ultrasound system used in this study 
and has agreed to provide organizational and limited support for this study: 
 
Exact Imaging Inc. 
7676 Woodbine Avenue, Unit 15 
Markham, ON 
L3R 2N2 
Canada 
 
Primary contact 
Brian Wodlinger 
VP, Engineering & Clinical 
bwodlinger@exactimaging.com 
Cell: (647) 527-9032 
Office: 905-415-0030 ext. 204 
Toll-free: 1-855-233-1919 ext. 204 
 
Secondary contact 
Andrea Matte 
Clinical Trial Monitor 
amatte@exactimaging.com 
Cell:  (416) 602-5012 
 
5.3.3 Identification of the investigators 
 
Investigators are identified on the site’s ethics’s approved informed consent form.  In addition, the 
study sites and investigators are listed on the ClinicalTrials.gov website.  The website is updated 
at least once yearly.  Address of the study site institution may be found in the signed clinical trial 
agreement (CTA). 
5.3.4 Overview of the investigational protocol 
The investigational protocol describes a study designed to compare the ability of ultra-high 
resolution transrectal micro-ultrasound (microUS) and multiparametric MRI (mpMRI)/US fusion to 
guide prostate biopsy.   

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Micro-ultrasound is a novel imaging modality that provides a dramatic improvement in ability to 
visualize abnormalities of the prostate compared to conventional ultrasound imaging.  This 
improvement in visualization has wide reaching consequences for clinical protocols from 
screening, through detection, and into treatment and treatment monitoring.  However, no 
randomized controlled evidence is available to compare the efficacy of microUS-guided prostate 
biopsy with the gold standard mpMRI/US fusion biopsy procedure. This investigational protocol 
aims to provide such evidence. 
 
The ExactVu device in particular, and micro-US in general have been studied in a number of other 
investigations, including a pilot study performed at Johns Hopkins University School of Medicine, 
in which differences between Ultra High Resolution (UHR) using ExactVu’s predecessor 
(ImagistxProstate) and Low Resolution (LR) transrectal ultrasound in their ability to detect 
cancerous foci in 25 patients were compared, along with safety and efficacy of this technology.1  
Three other previous studies have been approved through Western IRB, including protocol 
20131849 which provided the first randomized clinical trial on micro-US, Western IRB protocol 
20162036 which provided a small initial case series comparison of mpMRI and micro-ultrasound in 
the active surveillance population, and Western IRB protocol 20181898 compared micro-
ultrasound targeted biopsy to MRI targeted biopsy within the same patients.  Results from all 3 
studies were positive and 2 have recently been presented.2,3 Results from the 3rd as yet 
unpublished study are available on clinicaltrials.gov. 
  
Details about objectives of the investigation are described provided in section 5.7.1.  The 
investigational protocol was developed by a consortium of experts in prostate cancer early 
detection, and will be followed by the investigative team.  The Study Principal 
Investigator/Sponsor is responsible for the contents of the investigational protocol, and for 
monitoring the investigation. 
5.4 Device Description 
The ExactVu device is a new ultra-high resolution ultrasound system.  It uses a specialized high-
frequency transducer, developed by Exact Imaging Inc, to be used by qualified urologists, 
radiologists, and trained clinicians for real-time prostate imaging and biopsy procedures.  It also 
supports a customized low-frequency transducer.  The platform on which ExactVu operates 
represents the state of the art in high-resolution micro-ultrasound technology.  The ExactVu 
system first received pre-market clearance from the FDA on December 2nd 2016, and most 
recently on May 12th 2019 for the following indications for use (similar in Canada and Europe): 
The ExactVu High Resolution Micro-Ultrasound System is intended for use by qualified physicians, 
physician assistants, sonographers, and ultrasound technicians in a healthcare facility for 
diagnostic ultrasound imaging or fluid flow analysis of the human body in B-Mode (2D), Color Flow 
Imaging Modes (Color Doppler and Power Doppler) and Combined (B-Mode + CFI Modes). 
 
The indications for use are:  
• 
Small Organ  
• 
Transrectal  
• 
Abdominal The system may be used with patients of all ages, but is not designed for 
pediatric or fetal use. The system is contraindicated for direct cardiac application and for 
ophthalmic use or any application that causes the acoustic beam to pass through the eye. 
 

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The ExactVu device is also cleared for sale as a Class 3 device in Canada (Device Licence # 98667 
– ExactVu High Resolution Mico-Ultrasound System) and has received CE mark for Europe (CE 
2797) , both with the indication for diagnostic ultrasound imaging and prostate biopsy. 
For the purposes of this clinical investigation, the ExactVu device is being compared to a 
conventional-ultrasound-based mpMRI Fusion platform.  Like the ExactVu, this comparative Fusion 
platform has received pre-market clearance from the FDA, Health Canada, and CE mark.   
5.4.1 Device Identification  
Information for the Conventional Fusion Systems and transducers is located in Exhibit C of the 
Clinical Trial Agreement 
 
5.4.2 Purpose of the device in the context of the investigation 
For this investigation, both ExactVu and the conventional Fusion system will be used to perform 
the following tasks, consistent with their indications: 
 
Transrectal imaging of the prostate where clinically indicated (for example, for volume 
measurement or prior to biopsy) 
 
5.4.3 Materials that contact the patient 
The components of devices that will be in contact with tissues or body fluids include the sterile 
biopsy needle guide. 
 
During use, the transducers will be covered in a conductive coupling gel and covered by a sterile 
transducer sheath, and therefore will not be in direct contact with the patient.  If the sheath were 
to be compromised during the procedure, then the transducer, biopsy needle guide and biopsy 
needle could contact tissues or body fluids.  
5.4.3.1 
EV29L Transducer construction materials 
The materials used in the construction of the ExactVu transducer are: 
 
Rexolite by C-LEC Plastics – a polystyrene microwave plastic used for the transducer lens 
 
Epotek 301 – an epoxy used for gluing the housing sides together, and for gluing the lens 
to the housing 
 
PEEK LSG provided by Quadrant – a life sciences grade plastic used to construct the 
housing 
Each material has been tested on its own to meet applicable criteria of ISO 10993-1 – Biological 
evaluation of medical devices. 
 
The transducer may contact tissues or body fluids only if the sterile transducer sheath is 
compromised.   
5.4.3.2 
Biopsy needle guide construction materials 
The biopsy needle guide for use with EV29L is manufactured for Exact Imaging by CIVCO.  CIVCO 
is responsible for the selection of materials for this needle guide and for ensuring that the guide 
complies with the applicable criteria of ISO 10993 – Biological evaluation of medical devices. 
 
CIVCO is also responsible for completing sterilization and packaging validation. 

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5.4.3.3 
Qualified Gels 
This investigation recognizes Health Canada and FDA’s recommendations for the use of sterile gels 
for invasive procedures that pass a device through tissue (i.e., in biopsy procedures). 
Where non-sterile ultrasound gel is used, investigators must take steps to ensure that the product 
being used is not contaminated, and the container must be sealed appropriately when not in use.  
Gels whose packaging indicates that they are to be used for external procedures only must not be 
used.  Where non-sterile ultrasound gel is used, the use of single-dose gels is recommended. 
5.4.3.4 
Sterile transducer sheath 
Sterile transducer sheaths will be used for imaging procedures.  For biopsy procedures using the 
EV29L transducer, off-the-shelf sterile transducer sheaths will be supplied by Exact Imaging. 
5.4.3.5 
Transducer reprocessing 
Investigators will be provided with instructions for cleaning the ExactVu system and the high-level 
disinfection of applicable components.  These instructions meet the applicable criteria of FDA 
guidance documents regarding diagnostic ultrasound marketing/licensing. 
 
The instructions can be found in the document: 
 
Care, Cleaning and Use Guide for EV29L™ High Resolution Transrectal Side-fire Transducer 
 
Reprocessing of the competitive conventional Fusion system should be performed per 
manufacturer’s recommendations. 
5.4.4 Instructions for use 
Instructions for use for ExactVu and its accessories are provided in ExactVu labeling. 
 
Information describing the workflow for this this clinical investigation can be found in this CIP, 
which will be provided to investigators. 
5.4.5 Training requirements 
ExactVu is intended for use by qualified physicians and radiologists.  Its use does not require any 
additional training in medical procedures or principles of ultrasound technology. 
 
The investigators and applicable personnel that will participate in this clinical trial are familiar with 
the procedures that comprise this protocol, as they have already successfully completed training 
on the ExactVu platform and have used the high-frequency micro-ultrasound to visualize the 
prostate and guide prostate biopsy in clinical practice for more than 25 cases and have been 
certified as competent through Exact Imaging’s Mastery Program to at least Level 3 “Advanced 
User”.   
 
New training for the purposes of this protocol involves: 
 
An overview of the case report form, and the case data to be recorded  
 
This training will be documented on the training records that are controlled as per Exact Imaging 
standard operating procedures. 
 
Each investigator must complete this training before using ExactVu to perform biopsy procedures 
for this study.  
 

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5.4.6 Medical procedures 
Medical procedures to be performed in the study consist of subject preparation and imaging. The 
procedure will be the same for all subjects. 
 
The detailed procedure is as follows: 
1. Screening and consent visit (may be combined with visits 2 and/or 3): 
a. Patient meets inclusion criteria 
b. Patient willing to be randomized  
c. Informed consent and randomization 
2. Prior to biopsy (MRI/US and MRI/MicroUS arms only): 
a. Radiologist reads and annotates mpMRI for use during Fusion biopsy 
b. Annotated mpMRI is provided  
i. MRI/MicroUS arm: MRI is not shared with operator until unblinding 
3. Biopsy visit: 
a. Save sweep of prostate  
b. (MicroUS and MRI/MicroUS Arms) Record suspicious regions (PRI-MUS 3+)  
c. Standard of care biopsy 
i. Including targeted and systematic samples 
ii. Targeted samples must be potted and labeled separately per best practices 
d. Standard post-biopsy follow-up 
 
The subject is not required to come for additional clinic visits in the context of the study.   
 
Further healthcare decisions and follow-up are outside the scope of this study.  The subject’s 
participation in the study is completed 7 days following the biopsy session when they will be asked 
to answer a short questionnaire on their experience.  
5.5 Justification for the Design 
Conventional-ultrasound has demonstrated poor sensitivity for detection of prostate cancer, and 
this has translated to a standard systematic biopsy strategy which unfortunately still has an 
unacceptable 30% false negative rate.  Multi-parametric MRI has entered clinical use as a superior 
technique to conventional ultrasound, but still carries a 14% false negative rate4 and is 
significantly more expensive, requiring a second specialty to be involved in the care path.  While 
the technique is more sensitive it is not clear whether there is a strong enough relationship 
between the MRI abnormalities and the cancerous foci to merit its use for treatment planning, 
follow-up, and screening.  Improvements in prostate cancer imaging are needed. 
 
MicroUS uses high frequencies (29 MHz) to improve resolution of prostate ultrasound images, and 
provides a protocol for assessing risk in these images known as PRI-MUSTM (Prostate Risk 
Identification using Micro-Ultrasound)5. Using this technology, the predecessor of ExactVu was 
recently demonstrated by a team at Johns Hopkins Medical to have improved ability to image 
cancerous foci over conventional-ultrasound, and to have potential improved efficacy in identifying 
higher grade tumors1.  More recent studies have extended these findings, by providing further 
evidence of the superiority of micro-US to conventional-ultrasound2 and preliminary evidence that 
micro-US may provide similar improvements to mpMRI.3,6–8 
 
While single center and non-randomized studies support the hypothesis that micro-ultrasound 
provides similar biopsy quality to mpMRI, a higher level of evidence is required to change 
widespread clinical practice.  This study will provide the highest level of randomized controlled 
evidence to support the non-inferiority of microUS for biopsy guidance and additionally allow 

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estimation of the synergy between microUS and mpMRI to determine whether a combined 
approach is useful. 
5.5.1 Evaluation of pre-clinical data 
Exact Imaging has not performed pre-clinical testing using animals using the current version of 
ExactVu.  Tests using animals were performed prior to the pilot study described in section 5.5.2.1, 
using previous generations of the technology used in ExactVu, however these studies were not 
conducted by Exact Imaging.   
5.5.2 Clinical evaluation 
5.5.2.1 
Previous clinical experience:  Johns Hopkins Pilot Study 
Johns Hopkins Urology conducted a small-scale clinical trial in 2011/2012 using the previous 
generation of the technology used to design and manufacture ExactVu.  This trial was conducted 
to compare the differences between Ultra High Resolution (UHR) and Low Resolution (LR) 
transrectal ultrasound in their ability to detect cancerous foci in 20 patients. 
 
Patients were imaged pre-operatively with both micro-US and LR-TRUS. Areas of altered 
echogenicity ≥ 5mm on sagittal views were identified by a radiologist with an expertise in 
ultrasound blinded to pathology results. Actual areas of prostate cancer ≥5mm identified at 
sagittally-sectioned RP specimen were correlated to abnormal foci on both imaging modalities. 
Sensitivity and specificity analysis were performed for each imaging modality. A total of 56 
cancerous foci were pathologically identified. micro-US was superior to LR-TRUS in the 
identification of these foci (p = 0.01).  
 
The results of this pilot trial showed clinically meaningful increases in Sensitivity (56.5%), 
Specificity (21.1%) and PPV (predictive positive value) (42.0%) with ExactVu versus conventional 
low resolution ultrasound. 
 
Results of the study were published in Urologic Oncology1.  This protocol follows a similar design 
except using the current ExactVu instrument and with the addition of the PRI-MUS risk scale for 
consistent and repeatable analysis of the images.  Further, this protocol includes improved 
registration techniques to align pathology and imaging, new secondary outcomes, and neglects 
the conventional ultrasound comparator in favor of the improved pre-operative mpMRI. 
5.5.2.2 
Previous clinical experience:  Multi-Center trial of high-resolution 
transrectal ultrasound versus standard low-resolution transrectal 
ultrasound for the identification of clinically significant prostate cancer 
(2013-UHR-002) 
Exact Imaging recently conducted a large scale clinical trial (beginning in 2013, 2000 patients, 
under WIRB Protocol 20131849) to demonstrate that micro-US is superior to conventional LR-
TRUS in guiding prostate biopsies (systematic and targeted) among men without known prostate 
cancer and with an indication for prostate biopsy. 
 
Results from this trial have been analyzed and support the value of micro-US and the PRI-MUS 
protcol2.  Number and grade of adverse events between the micro-US and conventional 
ultrasound arms of the trial were identical (3 each).  2 of the three events in the micro-US arm 
were cases of post-biopsy bacteremia, suggesting a rate of 0.4% which is well within published 
rates for this procedure.  The third adverse event in the ExactVu arm was a patient who presented 
at the emergency room complaining of fever.  No fever was detected on admission, no elevation 

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in white blood cell count or growth in culture was found.  The patient was discharged the following 
day with a prolonged course of antibiotics despite the lack of evidence of infection.  All adverse 
events were anticipated events. 
 
5.5.2.3 
Previous clinical experience: Urology of Virginia Case Series (UHR-
2016-001) 
A small 9-subject case series was performed under WIRB protocol 20162036 to provide guidance 
to clinical users on the appearance of mpMRI lesions visualized with micro-ultrasound.  Results 
from this study were first presented at the EAU 2018 meeting and have recently been accepted 
for publication in the Canadian Urological Association Journal.3,9 
 
This small series demonstrated superior sensitivity by micro-US (89% vs 56% for mpMRI), 
particularly against relatively inexperienced mpMRI reviewers and for small Gleason Sum 7 
lesions.  Both micro-US and mpMRI provided superior targeting sensitivity compared to 
conventional ultrasound (p=0.02).  mpMRI lesions were retrospectively visible under micro-US, 
making it easier to perform accurate targeted biopsy. 
5.5.2.4 
Previous clinical experience: Reports in the literature from cohort 
studies 
Cohort studies are available from two European centers demonstrating promising detection rates 
and sensitivity relative to mpMRI.  Astobieta et al.6 reported on 41 consecutive subjects biopsied 
using the ExactVu micro-ultrasound system with available mpMRI studies for comparison and 
targeted biopsy.  mpMRI correctly predicted 28/41 subjects with clinically significant prostate 
cancer (68% sensitivity) while micro-ultrasound predicted 40/41 (98% sensitivity).  This 
improvement in sensitivity was significant with p<0.001. 
 
Similarly, Lughezzani et al10 reported on their first 60 subjects with both mpMRI targets and 
micro-ultrasound guided biopsy as part of their prospectively maintained prostate biopsy 
database.  In this dataset, in which all subjects had positive mpMRI, sensitivity and negative 
predictive value of micro-ultrasound were 83% and 80% respectively, while the sensitivity of 
mpMRI was similar at 85%.  This cohort was later updated to 320 subjects with equal detection 
rates of csPCa between mpMRI and MicroUS biopsy strategies (116/320 each).11 Wiemer et al12 
performed a similar study on 159 subjects undergoing biopsy with both mpMRI and microUS 
targets and found a 95% relative sensitivity for microUS targeted biopsy with significant added 
value on top of systematic and mpMRI targeted samples. 
 
5.5.2.5 
Previous clinical experience: Registry studies 
Klotz et al.13 published the experience of 1,040 biopsy procedures at 11 institutions.  In total 
39.5% of subjects were diagnosed with csPCa and both mpMRI and microUS were extremely 
sensitive to predict which would eventually be diagnosed (90% vs. 94%, microUS superior with 
p=0.03).  Specificity and PPV were similar between the two modalities though NPV was higher for 
microUS (85% vs. 77%).  The principal limitations here were the lack of randomization and lack of 
blinding at some centers due to the registry design. 
5.5.2.6 
Literature review 
A critical literature review was performed to establish the relative detection rates of prostate 
biopsy in the literature.  The conclusions for the evaluation are presented in section 5.20.  (Note 
that bibliographic references specific to the literature review are also presented in section 5.20.) 

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5.6 Risks and Benefits 
This clinical investigation will ensure that  
 
the residual risks, as identified in the latest revision of the risk and hazard analysis of the 
ExactVu system and 
 
risk(s) to the subject associated with the clinical procedure including follow-up procedures 
required by the CIP  
 
will be balanced against the anticipated benefits to the subjects.  
 
The sponsors will ensure that risk management shall be carried out and evaluated throughout the 
clinical investigation. 
5.6.1 Device risk analysis and management 
The Risk Management Plan for ExactVu and the related hazard analysis was conducted in 
accordance with the latest revision of ISO 14971 and with reference to Exact Imaging’s quality 
system procedures.  All anticipated adverse device effects are captured in the latest revision of 
the Risk and Hazards Analysis document of the ExactVu system.  
5.6.2 Risks associated with participation in the clinical investigation 
There are no known risks in the use of ultrasound as it will be used in this investigation.  There 
may be slight discomfort caused by the ultrasound probe inserted in a subject’s rectum, as in a 
standard imaging or biopsy procedure. The biopsy procedure itself carries certain risks, including 
sepsis, however these are beyond the scope of this investigation since the particular device used 
for imaging during the biopsy has no effect on these risks. 
 
5.6.3 Risks associated with the investigational device and its related 
clinical procedure 
Risks associated with the investigational device and its related clinical procedure shall be 
estimated in accordance with ISO 14971 prior to design and conduct of a clinical investigation. 
The risk assessment shall include or refer to an objective review of published and available 
unpublished medical and scientific literature as outlined in Section 5.5.2.6.  Note that the ExactVu 
device is cleared for sale in Canada, the United States, and has received CE mark for Europe, with 
the indication for diagnostic ultrasound imaging and prostate biopsy. 
When used in accordance with their Indications and Instructions for Use, the Risk-to-Benefit and 
Safety of the ExactVu System are deemed acceptable based on review of state-of-the-art 
literature covering the subject and equivalent device.  
 
As ExactVu System is used solely to image, the probable health benefit of the additional 
information provided outweighs the risk associated with its use. Thus, as the risks associated with 
the intended use of ExactVu System constitute acceptable risks when weighed against the benefits 
to the patient and are compatible with a high level of protection of health and safety, and 
conforms to MDD Essential Requirement 1, and MDR GSPR 8..  
 
Similarly, all anticipated adverse device effects shall be disclosed in the informed consent form. 
 

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5.6.4 Possible interactions with concomitant medical treatments 
No new interactions with concomitant medical treatments are anticipated related to the use of 
ExactVu.  ExactVu is already intended and cleared by FDA to perform the prostate imaging 
procedure clinically.  ExactVu is designed to introduce no increased risk when compared to 
conventional ultrasound.   
 
5.6.5 Risks associated with the Clinical investigation process 
Risk management will be applied to both the planning and the conduct of clinical 
investigations, in order to ensure the reliability of the clinical data generated and the safety of 
subjects. 
 
The sponsor shall identify, assess and control risks associated with clinical investigation processes 
to ensure the ethical and scientific conduct of the clinical investigation and the credibility of the 
clinical investigation results. 
 
Clinical risks related to the clinical procedures, including follow-up procedures required by the CIP 
other than those related to the medical device, shall be identified from the literature review and 
their disclosure in the CIP and if applicable, the informed consent, shall be determined by the 
sponsor and managed in the interest of subject safety. 
 
The sponsor will also consider applicability of Risk control measures at the clinical quality 
management system level, clinical investigation planning and conduct level (e.g., clinical 
investigation design, data collection, informed consent process)  
5.6.6 Steps that will be taken to control or mitigate the risks  
The latest revision of the Risk and Hazards Analysis document of the ExactVu system will outline 
the necessary design control and other mitigations taken to mitigate or lessen the risk probability 
number of the hazards identified. 
 
In addition, the latest revision of the Risk and Hazards Analysis document of the ExactVu system 
will also outline a rationale for the benefit-risk ratio. 
 
5.7 Objectives and Hypothesis 
5.7.1 Objectives 
Primary Outcome: Difference in detection rate of Grade Group > 1 Prostate cancers (csPCa) 
found using MicroUS + systematic biopsy and using mpMRI/US Fusion + systematic biopsy. 
 
Secondary (powered) Outcome: Difference in detection rate of Grade Group > 1 Prostate 
cancers (csPCa) found using MicroUS + mpMRI + systematic biopsy vs. mpMRI/US Fusion + 
systematic biopsy. 
 
Secondary (unpowered) Outcomes: 
 
Difference in negative predictive value of highest risk score per patient (PI-RADS or PRI-
MUS) for prediction of csPCa on biopsy 
 
Added value of each biopsy technique 

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 
Added value of systematic biopsy over targeted biopsy 
 
Difference in health economic variables: 
o 
Procedure time 
o 
Cost (including MRI scan / MRI Magnet time) 
o 
Radiologist time 
 
Patient Satisfaction 
 
Subpopulation analysis of men in the MicroUS-only arm with prior MRI vs those without 
 
5.7.2 Hypothesis 
Primary Hypothesis: The micro-ultrasound biopsy procedure is non-inferior to the mpMRI/US 
fusion biopsy procedure with a threshold of 10% and thus reduce the need for MRI prior to biopsy. 
5.7.3 Claims 
There are no claims related to the intended performance of the system that are to be verified in 
the analysis related to this investigation, aside from those related to the objectives. 
5.7.4 Risks 
There are no risks or foreseeable adverse device effects that are to be assessed in the 
investigation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.8 Design of the Clinical Investigation 
5.8.1 General 
5.8.1.1 
Type of clinical investigation 
The investigation is a randomized controlled study where all subjects have an indication for 
prostate biopsy.  A 3-arm randomization with unequal weighting will be used to compare three 
biopsy strategies: MicroUS only, n, MRI/US fusion, MRI/MicroUS (“FusionVu”) fusion.  The overall 
study schema is presented below. 
 
 
 

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5.8.1.2 
Avoiding bias 
The imaging scans will be saved for later analysis.  To avoid bias from a single operator 
performing the scan, multiple readers may be asked to comment on the image quality.   
 
5.8.1.3 
Endpoints 
Primary endpoint 
Number of men diagnosed with csPCa based on the pathology samples collected during the biopsy 
procedure through: 
- 
MicroUS samples (targeted and systematic samples taken under microUS imaging only 
without mpMRI) 
- 
mpMRI/US Fusion samples (targeted and systematic samples taken under conventional 
ultrasound imaging with mpMRI targets) 
 
Secondary endpoints 
As above, with the addition of combined results for men undergoing Fusion biopsy on the microUS 
system: 
- 
mpMRI/MicroUS samples (targeted and systematic samples taken under microUS imaging 
with mpMRI) 
5.8.1.4 
Variables 
The primary analysis will be performed at subject level.   
5.8.1.5 
Assessing variables 
The analysis to be performed on data collected during the investigation will be done using a 
generally accepted statistical software package such as MATLAB, R, SPSS, or SAAS.  The software 
will not be ‘calibrated’ other than if there are instances where the software does not perform as 
required against unusual or exceptional data. 
 
5.8.1.6 
Replacing subjects 
Case data for all enrolled study subjects will be included in the analyses.  Because a subject’s 
involvement ends following biopsy, and because it is not expected that a subject will drop-out 
after this procedure, the need to replace subjects is expected to be unlikely. 
 
If a subject needs to be replaced, they will be consented as per processes described for all study 
subjects. 
 
5.8.2 Medical devices and comparators 
See section 5.4. 
5.8.3 Subjects 
5.8.3.1 
Inclusion criteria for subject selection 
Subjects will be recruited to participate in the investigation as follows: 
1. Men indicated for prostate biopsy due to elevated PSA and/or abnormal DRE 

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2. No history of prior prostate biopsy 
3. No history of genitourinary cancer, including prostate cancer 
4. ≥18 years of age 
5. No contraindications to biopsy 
6. No contraindications to mpMRI 
7. No history of mpMRI for clinical investigation of prostate cancer within 12 months prior to 
screening and enrollment in the study   
5.8.3.2 
Exclusion criteria for subject selection 
Subjects will be excluded from being included in the investigation if any of the following is true: 
1. History of prior prostate biopsy 
2. History of genitourinary cancer, including prostate cancer 
3. Contraindications to biopsy 
4. Contraindications to mpMRI 
5.8.3.3 
Criteria and procedures for subject withdrawal or 
discontinuation 
Subjects may withdraw from the investigation at any time with no effect on their future care.   
 
If a subject wishes to stop participating in the investigation, they are to do so by notifying the 
Principal Investigator by phone or letter. 
 
If a subject withdraws from the investigation prior to having his biopsy procedure performed, the 
procedure will be performed as per the normal standard of care.  There will be no further follow-
up with this subject in the context of this investigation. 
 
Data considerations for this case are provided in section 5.9. 
5.8.3.4 
Point of enrolment 
Men meeting the criteria defined in section 5.8.3.1 will be asked to participate in the study and 
will be presented with a Research Subject Information and Consent Form.   
 
Subjects are considered to be enrolled in the investigation when they return a signed Research 
Subject Information and Consent Form to the Principal Investigator.   
 
When a signed form is presented, the subject agrees to join the investigation, and accepts the 
provisions on the form, including an understanding that he may leave the investigation at any 
time. 
5.8.3.5 
Total expected duration of the clinical investigation 
The investigation is expected to take approximately 2 years maximum.  
5.8.3.6 
Expected duration of each subject's participation 
The procedure follows the standard of care, in that it is performed immediately before a clinically 
indicated transrectal imaging procedure.  Subjects are not required to come for additional clinic 
visits in the context of the investigation.   
 
Participating in the trial will add approximately 2 minutes to the subject’s procedure time. 

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5.8.3.7 
Number of subjects  
The number of subjects to be included in the trial is 1200 across all participating sites.  ESites will 
be allocated between 30-200subjects. 
 
5.8.3.8  
Estimated time needed to select this number (i.e. enrolment 
period) 
The investigation is expected to take approximately 2 years total.  This is intended to provide 
adequate time to enroll and study the projected number of subjects in the trial.   A subject’s 
participation in the investigation is completed following the follow up survey 7 days post biopsy. 
 
5.8.4 Procedures 
5.8.4.1 
Clinical investigation-related procedures 
The procedures affecting subjects and investigators participating in the investigation are: 
- 
Consent / Subject Enrolment as described in section 5.15 
- 
Training as described in section 5.4.5 
- 
Medical procedure as described in section 5.4.6 
- 
Record Data on Case Report Forms as described in section 5.8.6 
- 
Analyze Data as described in section 5.9 
5.8.4.2 
Sponsor activities 
This is an investigator-initiated study, and the international group of Principal Investigators are 
responsible for this clinical investigation including the preparation of this CIP.  These 
responsibilities are presented in detail, to facilitate planning of this investigation. 
 
Exact Imaging will provide assistance in accordance with an approved budget that is incorporated 
into the Clinical Trial Agreement. 
 
Further detailed sponsor responsibilities can be found in Appendix A. 
5.8.4.3 
Compromising factors 
There are no known foreseeable subject-related factors such as subject baseline characteristics 
and lifestyle that may compromise outcomes or the interpretation of results. 
5.8.4.4 
Follow-up period 
Following a subject’s procedure, there is no further physical follow-up involved in the context of 
this investigation. 
5.8.4.5 
Post-investigation care 
No further medical care is provided within the context of this investigation.   
5.8.5 Monitoring Plan 
A risk-based monitoring plan shall be developed by the sponsor which will be tailored according to 
the stage of clinical development and the type of clinical investigation. 
The sponsor shall ensure, through oversight of the clinical investigation and timely adverse event 

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reporting, that unanticipated adverse device effects are identified and investigated rapidly so that, 
where necessary, additional risk control measures can be implemented. With the outcome of the 
risk assessment, a monitoring plan shall be developed outlining: 
 
a) the risks associated with the clinical investigation and adequate information on relevant 
risk control measures; 
b) the processes that need to be monitored including data that is required to be verified in 
source documents; 
c) the monitoring methods (on-site, a combination of on-site and where justified, centralized 
monitoring, as appropriate); 
d) the responsibilities; 
e) the procedures and requirements for the investigation's oversight; 
f) the methods for documenting and communicating monitoring results; 
g) the methods for obtaining compliance; 
h) the process for escalation in case of continuous or egregious non-compliance; 
i) those aspects of the clinical investigation which need special attention because if 
performed incorrectly or inadequately, would compromise the protection of human subjects 
or the integrity of the data; 
j) special requirements regarding personal data protection. 
 
The Study Monitor role for the clinical investigation will be provided by the sponsor. The sponsor 
will determine the extent and nature of monitoring for the clinical investigation that will be based 
on continuing risk assessment. The Study Monitor will adhere to the monitoring responsibilities, 
which include verifying that: 
 
a) compliance with the CIP is maintained and any deviation from the CIP is discussed with the 
clinical investigators, documented and reported to the group of Principal Investigators, 
b) the device is being used according to the CIP, and if modifications are required either to 
the device or its method of use or to the CIP, this need is reported to the group of Principal 
Investigators, 
c) the clinical investigators have and continues to have staff and facilities to conduct the 
clinical investigation safely and effectively, 
d) the clinical investigators have and continues to have access to an adequate number of 
subjects and devices, 
e) signed and dated informed consent forms have been obtained from each subject at the 
time of enrolment and before any study-related procedures are undertaken, 
f) the data in the case report forms are complete, are recorded in a timely manner and are 
consistent with the source data, the procedures for recording and reporting adverse events 
and adverse device effects to the sponsor are followed, 
g) there is a process in place for device accountability and traceability and that it is 
maintained, 
h) maintenance and calibration of the equipment relevant for the assessment of the clinical 
investigation is performed and documented, 
i) subject withdrawal and/or non-compliance is documented and discussed with the clinical 
investigator and reported to the group of Principal Investigators, 
j) findings of non-compliance or required modifications shall be reviewed with the 
investigator and disclosed in a written monitoring report to the group of Principal 
Investigators. 
 
Source data will be recorded on case report forms (CRFs) as described in section 5.8.6. 

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5.8.5.1 
Site Visits 
Further to Exact Imaging’s role for the investigation, Exact Imaging will provide support to ensure 
the quality of data related to the investigation by: 
 
on-site visits to each site at the beginning and end of the study, and as required to ensure 
optimal image quality and assist with protocol training 
 
thorough review of CRF data to identify and follow-up on missing data, inconsistent data, 
data outliers, and potential CIP deviations that may be indicative of systemic or significant 
errors in data collection and reporting and as determined by the study sponsor 
 
An on-site visit at the beginning of the investigation will include the following activities:  
1. Review of supplies required for the investigation 
a. Check that there continues to be an adequate supply of sterile transducer 
sheaths and needle guides 
 
2. Review of device maintenance and image quality assessment to ensure devices are 
functioning correctly 
 
3. Review issues with investigators 
a. Discuss and investigate any performance issues and device deficiencies and 
resolved as required.  These issues will be documented according to Exact Imaging 
service procedures including details about steps taken to resolve issues 
b. Review any changes to the investigative team and update details in the CIP as 
required 
c. Provide training where changes to the investigative team requires it 
 
Any on-site visits during the investigation will include the following activities:  
1. Review subject enrolment 
 
2. Review study data 
a. Review data collected on CRF 
b. Check CRF for completeness and accuracy.  Ensure CRFs are filled out properly 
c. Check ExactVu for images.  There must be at least one image saved on the system 
to correspond to each subject. 
d. Verify data.  Compare images stored on ultrasound system with CRF data and 
pathology report 
 
3. Copy and collect image data 
 
4. Copy and collect completed CRFs 
 
Along with providing assurance of the quality of investigational data, these actions will allow Exact 
Imaging to assess compliance with the CIP and required procedures.  Exact Imaging staff will 
make all documentation and reports from these visits available to the site Study Monitor for 
inclusion in study records as required. 
 
For cases in which Exact Imaging personnel observe biopsy procedures during a site visit, they 
shall neither perform medical procedures nor contact the study subject, but will provide support 
through instruction where required.  

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5.8.6 Case Report Forms 
The case report form(CRF) to be used in this investigation is designed to collect information about 
the subject medical history and the necessary primary endpoints for the primary analysis.  Paper 
CRF may be used to record data however; if they are used they will be considered source data.  
 
Source data will be recorded as follows: 
 
Subject demographics (de-identified) 
 
Genitourinary surgical/medical history 
 
Biopsy note taking form (optional paper form for taking notes during biopsy procedure) 
 
Survey questions to be completed following biopsy 
Along with the data accuracy checks listed above, Exact Imaging will also check data prior to and 
during analysis as follows: 
 
Logic checks on data, and follow-up on unusual data.   
 
Analysis of data is described in the subsections of section 5.9. 
 
The case report form to be used in this investigation was drafted collaboratively with the group of 
Principal Investigators and is controlled as per Exact Imaging’s standard operating procedures.    
5.8.7   Identity of study subjects 
At all times throughout the clinical investigation confidentiality shall be observed by all parties 
involved. All data shall be secured against unauthorized access.  Privacy and confidentiality of 
information about each subject shall be preserved in the reports and any publication of the clinical 
investigation data.   
 
It is the responsibility of the Study Coordinator under supervision of the Principal Investigator(PI) 
to maintain the privacy of the subject throughout the investigation.  The Study Coordinator or PI 
will make a subject’s personal information available to the appropriate parties, should it be 
required for monitoring, auditing or inspection by the Ethics Board/IRB if applicable.  
 
It is the responsibility of the study site to de-identify subjects, and provide the resulting subject 
identifier to those involved with the analysis of the case data.  This subject identifier will be 
recorded on CRFs, on ExactVu, and on pathology records.  Lists of subjects' names and identifying 
information will be maintained separately from case report forms, and will be accessible to the 
Study Coordinator (or designate). 
 
Similar de-identification will be applied to any DICOM imaging files that may exist for a subject 
and that may be used by to analyze case data. 
 
Centre 
De-identification scheme 
Centres are 
listed using 2 or 
3 unique letters 
On CRFs and on the ultrasound system(s) subjects will be identified 
alphanumerically and sequentially, using Site Centre-01, Site Centre-
02, etc. 
 
5.9 Statistical considerations 
5.9.1   Statistical design, method and analytical procedures 
Case data will be analyzed using Excel and MATLAB or other standard statistical software package.   

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Overall number of subjects diagnosed with csPCa in the MRI/US arm will be compared to number 
of subjects diagnosed with csPCa using microUS targeted and systematic biopsy samples in the 
MicroUS and MRI/MicroUS arms (i.e. discounting the MRI targeted samples taken after blinding in 
the MRI/MicroUS arm).  A non-inferiority threshold of 10% will be used.  Assuming a csPCa 
detection rate of 43% in each group, 1082 subjects are needed for 90% power. 
 
For the secondary fusion comparison overall number of patients diagnosed with csPCa will be 
compared between MRI/US Arm and MRI/MicroUS Arm with a non-inferiority threshold of 10%.  
Assuming a csPCa detection rate of 42% in the MRI/US Arm and 44% in the MRI/MicroUS Arm 
358 subjects per group is required for 90% power. 
 
Details of the design are presented in section 5.8.1.  
5.9.2   Sample size 
The trial will include 1200 subjects as per the table below.  
 
 
Endpoints 
MRI/US Arm 
MicroUS Arm 
MRI/MicroUS Arm 
Primary – MRI vs. MicroUS 
541 
541 
Secondary – Fusion Comparison 
358 
- 
358 
Minimum Sample Size (N=1082) 
541 
183 
358 
Proposed Sample Size (N=1200) 
600 
200 
400 
Proposed Randomization Ratios 
3 
1 
2 
 
It is not anticipated that additional subjects will be required, however if a subject drops out before 
the biopsy procedure they may be replaced as described in section 5.8.1.6. 
5.9.3   Level of significance and power of the clinical investigation 
Assuming a csPCa detection rate of 43% in each group, 1082 subjects are needed for 90% power 
to demonstrate that the lower bound of the two-sided 95% confidence interval is greater than the 
10% non-inferiority threshold. 
 
R and/or MATLAB software were used for sample size calculations.   
5.9.4   Expected drop-out rates 
Factors affecting possible drop-out rates include the option to withdraw participation at any time.  
 
It is anticipated that a subject’s inclination to withdraw at procedure-time will be minimal, as 
prostate biopsy is indicated clinically. 
 

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5.9.5 Pass/fail criteria 
The primary outcome of the study will fail if the number of subjects diagnosed with csPCa is more 
than 10% lower than the number of subjects diagnosed with csPCa in the MRI/US arm.  This will 
be quantified by testing against the lower two-sided 95% confidence interval bound for the 
difference. 
 
5.9.6   Criteria for the termination of the clinical investigation 
The investigation may stop early for success if the primary objective if proven with p<0.0026 at 
an interim analysis performed at 50% recruitment.  This was calculated using O’Brien-Fleming 
bounds, and lowers the maximum p-value at final analysis from 0.025 to 0.024. 
 
If the investigation is terminated early, no follow-up with subjects is required, since the standard 
of care for patients anticipating prostate biopsy is not affected by early termination. 
5.9.7   Procedures for reporting deviation from the statistical plan 
Where the analysis of case data does not handle unexpected data, Exact Imaging in conjunction 
with the Principal Investigators and 3rd party biostatistician will establish a strategy to modify the 
analysis algorithm and apply it to all data.  Such modifications will include validation of the 
algorithm prior to its acceptance for use. 
 
These modifications will be updated and described in the CIP, and/or as in the final report (as 
appropriate) along with justification for them. 
5.9.8 Specification of subgroups for analysis 
A subgroup analysis is planned for men in the MicroUS arm of the study who deviate from protocol 
by having prior mpMRI available.  This analysis will be used to demonstrate whether or not this 
group is consistent with the group of men in the MicroUS arm who are mpMRI naïve. 
5.9.9 Procedures that take into account all data 
Statistical analyses around study endpoints will not include data for subjects who are withdrawn 
(before or after their biopsy) or for whom the collected study data is incomplete. 
5.9.10 
Treatment of missing, unused data 
If a study subject withdraws from the main trial prior to imaging, his consent form will be 
retained, and the reason for exclusion of the data will be handwritten on the form as “withdrawn 
prior to imaging”. Similarly, if a study subject withdraws from the main trial following his imaging, 
his consent form and CRF will be retained, and both will be marked “withdrawn following 
imaging”. 
 
This will allow data to be collected about the number of patients that withdrew from the 
investigation prior to the imaging procedure, and the number that withdrew after the procedure.  
 
The same process will be applied to any circumstance of incomplete or incorrect data, with an 
indicator handwritten on his consent form and CRF to provide information about why the record is 
not used for analysis. 

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5.9.11 
Exclusion of data 
Conditions that would result in the exclusion of data would be if any data verification activity 
showed that data was recorded on the CRF incorrectly, or if the pathology report showed any 
inconsistency with information on the CRF. 
 
If such incorrect data was discovered, data for this subject will not be included in any analysis, 
and the CRF for the subject will be marked to indicate that the data is excluded.  
5.9.12 
Subjects at multi-center investigations 
This information is provided in section 5.8.3.7. 
5.10 Data Management 
Data will be stored on electronic CRFs using an Electronic Data Capture system, and exported to 
an analysis tool (Excel by Microsoft and/or MATLAB by Mathworks Inc.).   
 
No subject-identifiable information will be transferred.  Instead, study data pertaining to a 
particular subject will be entered using a de-identified alphanumeric subject code.  This is 
described further in section 5.8.7.   
 
Analysis data will be backed-up in accordance with Exact Imaging’s standard operating 
procedures.   
5.10.1 
Data review 
Source data will be verified by the Study Monitor, as described in section 5.8.5.1.  
5.10.2 
Data verification and validation 
Source data will be recorded in the Electronic Data Base and/or on case report forms (CRFs) as 
described in section 5.8.6. 
 
Source data will be verified by the Study Monitor, as described in section 5.8.5.1. 
 
This data will be collected by the Study Coordinator or Study Monitor (collect de-identified films), 
and forwarded to Exact Imaging personnel for analysis.  The accuracy of the data will be verified 
by Exact Imaging by manual comparisons between: 
 
data on CRFs and on images stored on ExactVu 
5.10.3 
Data retention 
All documents related to this investigation will be handled in accordance with Exact Imaging’s 
quality system procedure QSP 4.2.3 Control of Documents.   This procedure describes the way 
Exact Imaging controls its documents in a way that involves a formal document review, approval 
and release process, and prevents outdated or obsolete documents from being used.  This 
procedure is designed to comply with the requirements of ISO 13485.   
 
Exact Imaging, and each Site Principal Investigator shall maintain the records collected during the 
investigation for a period of 2 years after the latter of the following two dates: the date on which 
the investigation is terminated or completed, or the date that the records are no longer required 

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for purposes of supporting a premarket approval application.  Institutions will retain data collected 
according to local institutional or applicable requirements of the Ethics Board/IRB.  
5.10.4 
Clinical quality assurance 
This CIP identifies the elements of quality control principles that Exact Imaging applies to this 
clinical investigation, including the descriptions of procedures that ensure the clinical investigation 
is designed, conducted and monitored in accordance with applicable regulations and the 
requirements of the Ethics Board/IRB. 
 
Exact Imaging maintains records to document the agreement of all parties involved in the 
investigation to the contents of this CIP. 
5.11 Amendments to the CIP 
All amendments to the CIP shall be agreed to between Exact Imaging and the study principal 
investigator and be recorded with a justification for the amendments. Deviations will be reviewed 
to determine the need to amend the CIP or to terminate the investigation. 
 
When there are changes to the initial list of clinical investigators this list will not be formally 
updated by amendments at each change; Exact Imaging will maintain an updated list which will 
be available on request.  The Ethics Board/IRB will be notified when required. 
 
5.12 Deviations from the CIP 
Investigators are not allowed to deviate from the CIP, except when the deviation is required to 
address the subject’s rights, safety and well-being, or the scientific integrity of the clinical 
investigation.  Any deviation from the CIP (this document) shall be recorded together with an 
explanation for the deviation.  Deviations shall be reported to Exact Imaging, who is responsible 
for analyzing them and assessing their significance with regards to risk and safety.  The CIP will 
be amended when the nature of the deviation requires it to be. 
 
The reasons for withdrawal and discontinuation of any subject from the investigation shall be 
recorded. 
 
Deviations will be recorded in the final report along with the justification for the deviation.  Where 
applicable, the Ethics Board/IRB will be notified. 
 
5.13 Device Accountability 
All devices used in this study are cleared for clinical use in the appropriate jurisdictions and are 
being used for their cleared indications. The devices used in this study are not hazardous and do 
not need any special procedures, particular materials nor any special instructions for the safe 
return after the clinical investigation is completed. 
 
5.14 Statements of Compliance 
This clinical investigation shall be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki. 

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This CIP and the investigation itself are designed to meet applicable requirements and regulations 
of the US FDA and other appropriate regulatory bodies for conducting clinical investigations. 
 
The investigation will not begin until the required approval is obtained from the Ethics Board/IRB. 
 
Any additional requirements imposed by the Ethics Board/IRB and/or the appropriate regulatory 
authority shall be followed  
5.15 Informed Consent Process 
This informed consent process is obtained by providing a potential study subject with an 
information sheet containing information about the purpose of the investigation, how to 
participate, benefits and risks, as well as information about the medical procedures to be 
performed.  When a potential study subject signs the consent form, he agrees to enroll in the 
investigation. This clinical investigation does not involve emergency treatment where prior 
informed consent of the subject is not possible because of the subject's medical condition. 
 
5.16 Adverse Events, Adverse device effects, and device deficiencies 
5.16.1 
Reporting adverse events 
Unanticipated adverse device effects during clinical investigations of devices will be reported as 
appropriate to Exact Imaging, the Ethics Board/IRB and investigators participating in the study. 
 
Exact Imaging will retain copies of adverse event reports as described in section 5.10.3. 
5.16.1.1 
Adverse event reporting process 
Exact Imaging follows an internal company procedure, Clinical Trial Incident Reporting Procedure, 
to assess and report adverse events and other incidents associated with the investigation. 
 
This process specified in this procedure is as follows: 
 
1. 
An investigator will report any incident to Exact Imaging as soon as possible, and no 
later than 5 working days after first learning of the event. 
2. 
Exact Imaging will conduct an evaluation of the incident, and determine the nature of 
the incident. 
3. 
Exact Imaging will follow the process for reporting to the Ethics Board/IRB as required 
within the required timeframe, and in the required format. 
5.16.1.2 
Adverse event report format 
Reports must follow the Ethics Board/IRB guidelines, and use the required reporting form.   
 
5.16.1.3 
Site Contacts  
Site contact information is located on the individual site’s approved Informed Consent Form (as 
per their ethics committee) and Clinical Trial Agreement 

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5.16.2 
Device deficiency reporting process 
If a device deficiency does not require immediate resolution, it will be discussed between the 
principal investigator, Study Monitor and Exact Imaging during the appropriate site visit, and 
resolved as described in section 5.8.5.1.   
 
If a device deficiency required immediate resolution, the principal investigator will report the issue 
to the Study Monitor and Exact Imaging by phone.  The Study Monitor will assess the issue, and 
work with Exact Imaging personnel to provide a solution or workaround in the necessary 
timeframe.  
5.16.3 
Foreseeable adverse events 
There are no foreseeable adverse events or adverse device effects related to the use of ExactVu in 
this investigation. 
5.17 Vulnerable population 
Considerations for vulnerable populations such as minors are not required, as the inclusion criteria 
related to age excludes this population automatically.  
 
Considerations for vulnerable populations such as those with potentially limited comprehension of 
research methods are not required, as enrolled subjects would undergo prostate biopsy regardless 
of whether or not they participate in the investigation. 
 
Considerations for vulnerable populations such as those with language or cultural barriers are not 
required, as enrolled subjects would undergo prostate biopsy regardless of whether or not they 
participate in the investigation, and it is assumed they would have taken steps to comprehend the 
contents of the Patient Information and Consent form prior to signing it. 
 
Considerations for vulnerable populations such as those that are socially or economically 
disadvantaged that participation in medical research is viewed as the only option to access 
otherwise unavailable medical treatment are not required, as enrolled subjects would undergo 
prostate biopsy regardless of whether or not they participate in the investigation. 
5.18 Suspension or premature termination of the clinical investigation 
If patients are harmed in any way this trial will be halted until the cause is identified and 
measures taken to correct it.  The Ethics Board/IRB and any other affected regulatory body will be 
notified in accordance with section 5.16.  
 
In the event that the investigation is terminated early, Exact Imaging will collect case report form 
data for consideration towards future clinical investigations.  The Ethics Board/IRB shall be 
informed promptly and provided with the reason(s) for the termination. 
5.19 Publication policy 
Exact Imaging encourages the investigators to publish the results of this clinical investigation to 
reputable journals. 
 
The conditions by which the results may be published are: 

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 
Investigators are required to advise Exact Imaging of their intention to publish an article 
related to the results of the investigation. 
 
Exact Imaging requires the opportunity to review any articles pertaining to the results of 
the study prior to publication. 
 
All Site Principal Investigators and Study Principal Investigator must provide consent, in 
writing, prior to manuscript submission. 
 
No subject will be identifiable in any published results. 
 
5.20 Critical Literature Review 
(Literature reviewed July 28 2021) 
 
Introduction and Objective 
Significant data is available on both the effectiveness of standard of care mpMRI biopsy and 
micro-ultrasound biopsy.  This critical literature review aims to analyze the available data on these 
techniques in order to estimate the detection rates of csPCa in this study and the difference in 
detection rate that would be clinically important. 
 
Methodology 
General 
Clinical guidelines from the AUA, EAU, and NCCN were used as the starting point for this review.  
All relevant citations used in the acceptance of mpMRI as the recommended strategy for biopsy 
were reviewed.   
 
The PubMed/Medline and Google Scholar databases were used to identify relevant literature on 
micro-ultrasound, in addition to unpublished data held by the manufacturer.  Search terms 
included: 
 
Prostate, Ultra High Resolution Ultrasound, High Frequency Ultrasound, High Resolution 
Ultrasound, micro-ultrasound, PRI-MUS 
 
Selection criteria for documents 
All relevant data from studies with similar procedure, inclusion and exclusion criteria will be 
included.  Studies involving similar ultra-high resolution ultrasound devices will be included, as 
well as those using standard low resolution ultrasound.  Where the results are still relevant to the 
review, deviations in procedure or inclusion will be discussed for each study or group of studies.    
 
Critical evaluation of literature 
The most common technique for diagnosis of prostate cancer involves screening based on 
prostate specific antigen (PSA), followed by systematically spacing biopsy samples throughout the 
gland in men at risk.  Unfortunately, this systematic biopsy procedure has a sensitivity of only 
48% to detect clinically significant prostate cancer (csPCa) compared to template mapping 
biopsy4, and a 30% rate of underestimating the risk profile of the cancer when it is found14.  Men 
undergoing this systematic biopsy pathway are at risk of underdiagnosis, resulting in a delay to 
appropriate treatment, increased risk of prostate cancer mortality, and an unnecessary exposure 
to the morbidity of repeat biopsy.15–17  While various strategies including both advanced imaging 
and biomarkers are available to refine the population exposed to biopsy-related morbidity, 
improved biopsy guidance is necessary to ensure these men receive appropriate therapy matched 
to the true aggressiveness of their disease.  
Multiparametric MRI (mpMRI) targeted biopsy has been extensively studied as a solution to this 
problem and represents a clear improvement over systematic biopsy.18–21  According to a 

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Cochrane review on the subject, the addition of mpMRI targeting improved detection of csPCa by 
5% over systematic biopsy in biopsy naïve men.22 A meta-analysis by Goldberg showed a greater 
impact with a 7-18% improvement.23  Similar reductions in upgrading have also been 
demonstrated, lowering the upgrading rate on radical prostatectomy from 30% to 6.7%.14 
 
Table 1 - Efficacy of additional mpMRI-directed samples over Systematic biopsy alone.  Improvement in 
csPca detection ranges from 5% to 18% while overall detection rate ranges from 30%-61%. 
Study 
MRI+Sys 
csPCa  
Sys 
csPCa 
Difference 
Limitations 
Cochrane meta-
analysis22 
53% 
48% 
5% 
 
Goldberg et al. 
meta-analysis23 
N/A 
N/A 
7-18% (11% 
in RCTs) 
 
Valerio et al. meta-
analysis24 
36% 
26% 
9% 
 
Variability in csPCa definition and 
inclusion of prior neg biopsy 
Kasivisvanathan et 
al.  meta-analysis25 
40% 
27% 
12% 
Variability in csPCa definition and 
inclusion of prior neg biopsy 
PRECISE26 
35% 
30% 
5% 
Targeted biopsy only on MRI 
MRI-FIRST18 
37% 
30% 
7% 
 
PAIREDCAP27 
61% 
52% 
9% 
 
PRECISION28 
38% 
26% 
12% 
No systematic samples in MRI 
group 
PROMIS4 
37% 
22% 
15% 
No MRI targeted biopsy 
4M21 
30% 
23% 
7% 
In-bore MRI sampling rather 
than MRI/US fusion 
ASIST29 
33% 
27% 
6% 
Active Surveillance population 
 
The mpMRI-informed diagnostic pathway 
The American Urology Association, European Association of Urology, and National Comprehensive 
Cancer Network all recognize the use of mpMRI in order to improve the efficacy of the prostate 
biopsy procedure.30–32 However, mpMRI targeted biopsy still misses small high grade cancers and 
up to 20% of GG2 cancers4,18,20.  These groups agree that mpMRI targeted biopsy should be 
combined with systematic biopsy in order to optimize the procedure, and that systematic biopsy 
should still be performed in the event of negative mpMRI but persistent clinical suspicion of 
cancer.   
The inclusion of mpMRI has altered the diagnostic pathway by requiring a cohort of expert 
radiologists specializing in prostate MRI to meet the demand.  The care pathway has also required 
changes to include referral to radiology after (and, in some settings, before) initial consultation 
with the urologist. 
These changes to the patient care pathway have introduced new sources of error and delayed 
diagnosis in many places.  In the UK for example, the median time to diagnosis is 55.5 days.33  At 
one prostate diagnostic clinic, the time-to-diagnosis was significantly lower in patients who did not 
receive mpMRI compared to those that did (15 vs. 22 days).33  This discrepancy is greater in 
centers which have pre-existing resource constraints. 
Variability in care has been exacerbated by the reliance on mpMRI due to significant and wide-
spread inter-reader variability.  Pickersgill et al. found poor agreement and poor accuracy among 
blinded radiologists for PI-RADS score and prediction of csPCa.34  Similarly, Westphalen et al. 
found a large 27%–44% variability in the targeted detection rate (positive predictive value) of 
MRI-targeted biopsy across 24 imaging centers.35  This increase in variability reduces confidence 
in the diagnostic process and may contribute to suboptimal results as mpMRI adoption increases.  
In the same way, the inclusion of MRI-derived data, along with the transfer of imaging data in 
pre-specified proprietary formats for fusion biopsy, adds complexity to the diagnostic pathway. 

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This represents a source of error.  The magnitude of this error has yet not been well quantified, 
but is likely to be substantial outside recognized centers of excellence.  
Further, mpMRI cannot be used in all men.  Among the contraindications are several conditions 
that are prevalent within the population at risk, including implanted devices such as pacemakers 
and hip replacements (hip prostheses alone represent up to 4%36), impaired kidney function 
(12%37), and claustrophobia (3-5%38).  These men are not candidates for the mpMRI diagnostic 
pathway. 
 
Micro-ultrasound imaging 
Micro-ultrasound (microUS) is a recently developed, real-time ultrasound-based modality 
operating at 29MHz compared to Conventional trans-rectal ultrasound systems at 6-9MHz.  Thus 
microUS results in a significantly higher resolution, 70 microns, which allows the underlying tissue 
structure to be visualized.1,39,40 At a resolution of 70 microns, alterations in ductal anatomy 
associated with higher grade cancer can be visualized, based on the same principle as restricted 
diffusion with MRI.   
Images are interpreted according to the PRI-MUS protocol (Figure 1). This evidence-based risk 
scale was initially validated5 in 2016, and a larger scale, prospective validation study41 confirmed 
these results in 2019.  The PRI-MUS protocol has similar risk stratification to the PI-RADS system 
for MRI.11 
 
 
Figure 1 - Example images demonstrating the various imaging features of the PRI-MUS protocol.  This risk-
stratification protocol grades images based on tissue patterns seen in micro-ultrasound from 1 (very low risk 
fo significant cancer) to 5 (very high risk of significant cancer). 
 
Micro-ultrasound and mpMRI fusion biopsy 
Due to the challenges of performing biopsy within the MRI gantry, MRI/US fusion biopsy is the 
more popular approach to sample targets identified by mpMRI.  However, aligning the mpMRI 

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data which is often taken on a different day and with the patient in a different position to the real-
time ultrasound is not trivial and may be complicated by pressure from the ultrasound transducer 
on the prostate causing deformation.  This procedure relies heavily on two factors to achieve 
accurate sampling: reliable position tracking and correction for soft tissue deformation.   
Micro-ultrasound has been hypothesized to improve the accuracy of mpMRI fusion biopsy by 
reducing the operator’s reliance on the position tracking and deformation calculations of their 
fusion platform.  Since micro-ultrasound is able to observe the majority of these suspicious areas 
natively, the operator is able to sample under direct real-time visual guidance rather than relying 
on the accuracy of the fused MRI images, or any pre-defined contouring.  This has been 
investigated by several groups (see Table 1Table 2), with Cornud et al. demonstrating that 
microUS was able to visualize 79% of all MRI targets natively and 100% of targets positive for 
csPCa.42 Perhaps because of this, Claros et al. reported a 15%  improvement in MRI-directed 
biopsy yield when comparing a robotic fusion platform with a microUS platform.43 
Micro-ultrasound may also find additional suspicious regions within the prostate, and these targets 
may further improve biopsy yields when added to the mpMRI fusion biopsy strategy.  This has 
been demonstrated by several groups, showing additional detection of csPCa in the 1-17% range 
(Table 2). 
Improving the accuracy of mpMRI-target sampling, removing contouring requirements, and 
finding additional targets that may have been missed on mpMRI would mitigate the complexity 
and variability in the mpMRI pathway. 
Table 2 - Recent studies adding microUS to mpMRI protocols 
Study 
Improvement 
Cornud et al.42 
79% of all mpMRI targets visualized, including 100% of csPCa 
targets. 
Claros et al.43 
15% improvement in MRI-targeted biopsy csPCa rate 
Wiemer et al.12 
17% added csPCa due to microUS targeted samples 
Lughezzani et al.11 
1% added csPCa due to microUS targeted samples 
Socarrás et al.44 
6% added csPCa due to microUS targeted samples 
 
Can micro-ultrasound avoid mpMRI fusion biopsy? 
In order to simplify the diagnostic pathway further, it would be desirable to replace mpMRI with a 
real-time modality of equal clinical utility.  This change would improve time to diagnosis, as well 
as access, by combining the imaging and biopsy steps.  In order for such a pathway to be 
acceptable it should maintain the accuracy of the mpMRI pathway for the detection of csPCa.   
Data available (see Table 3) on this topic include a large 11-center, 1040-subject registry study 
performing a direct comparison to mpMRI which concluded that the two techniques provided 
similar sensitivity and negative predictive value.13 Various other single-center studies and meta-
analyses have demonstrated similar rates of csPCa detection between mpMRI-guided and 
microUS-guided biopsy protocols.8,11,12,39,45,46 
Table 3 - Recent studies comparing microUS and mpMRI 
Study 
Metric 
MRI  
MicroUS 
Klotz et al.13  
Sensitivity 
90% 
94% 
Wiemer et al.12 
csPCa detection 
38% 
44% 
Lughezzani et al.11 
csPCa detection 
35% 
35% 
Socarrás et al.45 
csPCa detection 
28% 
24% 
Abouassaly et al.8 
Increase in csPCa 
detection 
N/A 
12% 
 
 
Calculation of Non-Inferiority Threshold and Expected Detection Rates 

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The non-inferiority threshold of 10% was determined by expert-consensus from the advisory 
panel involved in the creation of this protocol, however it is consistent with the improvement in 
csPCa rates observed in the literature for mpMRI over the previous standard of systematic biopsy 
(see Table 1).  The expected csPCa rates across the three arms of 42-44% were calculated based 
on pooled data from 414 biopsy naïve subjects with combined microUS and mpMRI biopsy across 
4 studies at 7 institutions. This data includes 1 previously published study11 and 3 studies which 
have been submitted for publication, and correlates well with the data from Table 1.   
 
Evaluation of hazards, risks and safety measures 
Risks associated with the biopsy procedure are well understood and outside the scope of this 
protocol since the biopsy procedure is clinically indicated and study procedures are not expected 
to modify these risks.  Risks associated with study data collection will be managed by the Study 
Monitor, as described in this CIP. 
 
Statistical and weighting methods 
All clinical studies were weighted based on enrollment numbers, unless otherwise stated or 
specifically excluded for differences in protocol or enrollment. Care was taken to identify studies 
with patients drawn from the same population which would not be independent. 
 
Conclusions 
Micro-US is a promising modality for TRUS-guided biopsy procedures which may offer improved 
workflow, reduced complexity in care pathway, reduced time-to-diagnosis, and reduced 
healthcare costs. Enrolment numbers are reasonable and consistent with other human studies in 
this area. 
5.21 Bibliography 
1.  
Pavlovich CP, Cornish TC, Mullins JK, et al. High-resolution transrectal ultrasound: Pilot study of a novel technique for imaging 
clinically localized prostate cancer. Urol Oncol. Published online April 1, 2013. doi:10.1016/j.urolonc.2013.01.006 
2.  
Hyndman M, Pavlovich C, Eure G, Fradet V, Ghai S. Prospective validation of PRI-MUSTM, the Prostate Risk Identification using 
Micro-Ultrasound protocol for real-time detection of prostate cancer using high-resolution micro-ultrasound imaging. In: 
American Urology Association. ; 2018. 
3.  
Eure G, Fanney D, Lin J, Ghai S. Comparison of conventional TRUS, MRI and micro-ultrasound for visualizing prostate cancer in 
an active surveillance population: A feasibility study. Eur Urol Suppl. 2017;16(9):e2614. doi:10.1016/S1569-9056(17)31763-3 
4.  
Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate 
cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;6736(16):1-8. doi:10.1016/S0140-6736(16)32401-1 
5.  
Ghai S, Eure G, Fradet V, et al. Assessing Cancer Risk on Novel 29 MHz Micro-Ultrasound Images of the Prostate: Creation of the 
Micro-Ultrasound Protocol for Prostate Risk Identification. J Urol. 2016;196(2):562-569. doi:10.1016/j.juro.2015.12.093 
6.  
Astobieta Odriozola A, Sanchez A, De La Cruz I, et al. Initial results comparing 29 MHz micro-ultrasound with multi-parametric 
MRI for targeted prostate biopsy: Relative sensitivity to clinically significant prostate cancer. Eur Urol Suppl. 2018;17(2):e901. 
doi:10.1016/S1569-9056(18)31462-3 
7.  
Lughezzani G, Saita A, Lazzeri M, et al. Comparison of the Diagnostic Accuracy of Micro-ultrasound and Magnetic Resonance 
Imaging/Ultrasound Fusion Targeted Biopsies for the Diagnosis of Clinically Significant Prostate Cancer. Eur Urol Oncol. 
2019;2(3):329-332. doi:10.1016/j.euo.2018.10.001 
8.  
Abouassaly R, Klein EA, El-Shefai A, Stephenson A. Impact of using 29 MHz high-resolution micro-ultrasound in real-time 
targeting of transrectal prostate biopsies: initial experience. World J Urol. 2019;(0123456789):1-6. doi:10.1007/s00345-019-
02863-y 
9.  
Eure G, Fanney D, Lin J, Wodlinger B, Ghai S. Comparison of Conventional TRUS, MRI and Micro-Ultrasound for Visualizing 
Prostate Cancer in an Active Surveillance Population: A Feasibility Study. Can Urol Assoc J. Published online 2018. 
10.  
Lughezzani G, Maffei D, Lazzeri M, et al. Comparison Between the Diagnostic Accuracy of Micro-Ultrasound Versus 
Multiparametric MRI in the Detection of Prostate Cancer: Preliminary Results from a Single-Institutional Ongoing Prospective 

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Trial. In: European Association of Urology. ; 2018. 
11.  
Lughezzani G, Maffei D, Saita A, et al. Diagnostic Accuracy of Microultrasound in Patients with a Suspicion of Prostate Cancer at 
Magnetic Resonance Imaging: A Single-institutional Prospective Study. Eur Urol Focus. Published online October 2020:1-8. 
doi:10.1016/j.euf.2020.09.013 
12.  
Wiemer L, Hollenbach M, Heckmann R, et al. Evolution of Targeted Prostate Biopsy by Adding Microultrasound to the Magnetic 
Resonance Imaging Pathway. Eur Urol Focus. Published online 2020:1-8. doi:10.1016/j.euf.2020.06.022 
13.  
Klotz L, Lughezzani G, Maffei D, et al. Comparison of micro-ultrasound and multiparametric magnetic resonance imaging for 
prostate cancer: A multicenter, prospective analysis. Can Urol Assoc J. 2020;15(1):1-13. doi:10.5489/cuaj.6712 
14.  
Ahdoot M, Wilbur AR, Reese SE, et al. MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis. N Engl J 
Med. 2020;382(10):917-928. doi:10.1056/NEJMoa1910038 
15.  
Emberton M. Is a negative prostate biopsy a risk factor for a prostate cancer related death? Lancet Oncol. 2017;18(2):162-163. 
doi:10.1016/S1470-2045(17)30024-4 
16.  
Neal DE, Metcalfe C, Donovan JL, et al. Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with 
Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received. Eur Urol. 
2019;77:331-332. doi:10.1016/j.eururo.2019.10.030 
17.  
Helgstrand JT, Røder MA, Klemann N, et al. Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic 
prostate cancer-A population-based analysis of 2 national cohorts. Cancer. 2018;124(14):2931-2938. doi:10.1002/cncr.31384 
18.  
Rouviere O, Puech P, Renard-Penna R, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric 
MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol. 2019;20(1):100-
109. doi:10.1016/S1470-2045(18)30569-2 
19.  
Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis (Supplement). 
N Engl J Med. Published online 2018:NEJMoa1801993. doi:10.1056/NEJMoa1801993 
20.  
Elkhoury FF, Felker ER, Kwan L, et al. Comparison of Targeted vs Systematic Prostate Biopsy in Men Who Are Biopsy Naive: The 
Prospective Assessment of Image Registration in the Diagnosis of Prostate Cancer (PAIREDCAP) Study. JAMA Surg. 
2019;154(9):811-818. doi:10.1001/jamasurg.2019.1734 
21.  
van der Leest M, Cornel E, Israël B, et al. Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy Versus 
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Appendix A 
Sponsor Responsibilities 
Clinical quality assurance and quality control 
Quality assurance and quality control principles shall apply to the processes of the clinical 
investigation. The sponsor shall: 
a. implement and maintain written clinical quality procedures to ensure that the clinical 
investigation is designed, conducted and monitored, and that data are generated, 
documented, recorded and reported in compliance with ISO 14155, the CIP, any 
subsequent amendment(s), and any other applicable standards and regulatory 
requirements 
b. maintain records to document the compliance of all parties involved in the clinical 
investigation 
c. ensure that the auditing requirements are met when applicable 
d. justify and document significant exceptions to the requirements identified in ISO 14155 
 
 
Selection of clinical personnel 
Prior to commencement of the clinical investigation, the sponsor shall: 
a. define, establish and allocate all the roles and responsibilities related to the clinical 
investigation in one or more written agreements 
b. select an appropriately qualified Principal Investigator 
c. receive disclosures of conflict of interest from principal investigators and investigators, 
where required by national regulations 
d. ensure the members of the investigation site team and their designated authorization(s) 
are identified in a log with details  
e. designate or appoint one or more monitors, or otherwise assume the responsibilities of the 
monitor(s) 
f. 
ensure documentation of training, experience and scientific or clinical knowledge for all the 
relevant parties involved in order to adequately conduct the clinical investigation, including 
training, on 
a. the use of the investigational device(s) 
b. device accountability procedures 
c. Investigator’s Brochure (same as Clinical Investigator Protocol) 
d. CIP 
e. CRFs and instructions for completion 
f. 
the written informed consent form and process as well as other written information 
provided to subjects 
g. sponsor's written procedures, ISO 14155 and any applicable regulatory 
requirements 
g. ensure that any clinical-investigation-related activities of sponsor representative(s) at the 
investigation site(s) are described in the CIP and the informed consent form, and that 
these activities occur in such a way that they do not bias the data integrity 
NOTE Individuals such as field engineers or sales representatives who will provide technical 
expertise in the implementation of the clinical investigation, are examples of sponsor 
representatives 
h. consider the need for a data monitoring committee and, if appropriate, establish the 
committee 
 
Preparation of documents and materials 
Prior to commencement of the clinical investigation, the sponsor shall: 

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a. prepare required documents and ensure they are approved by the relevant persons by 
dated signature; if required, copies shall be provided to all parties involved, and dated 
signatures obtained as appropriate 
b. ensure that a supply of investigational devices is available in a timely manner for the 
clinical investigation; investigational devices shall not be made available to the principal 
investigator until all requirements to start the clinical investigation are met 
c. provide insurance covering the cost of treatment of subjects in the event of clinical-
investigation-related injuries, in accordance with the national regulations if applicable, 
d. document any financial arrangements between the principal investigator or the 
investigation site and the sponsor 
e. submit any required application(s) to begin the clinical investigation in a given country to 
the appropriate regulatory authority(ies) for review, acceptance or permission [as per 
applicable regulatory requirement(s)] 
f. 
ensure that the Ethics Board/IRB approval/favourable opinion is obtained and documented, 
and that appropriate provisions are made to meet any conditions imposed by the Ethics 
Board/IRB 
g. ensure that any modification(s) required by Ethics Board/IRB or regulatory authority are 
made and documented by the Principal Investigator and have gained the 
approval/favourable opinion of the Ethics Board/IRB or regulatory authority 
 
Conduct of clinical investigation 
The sponsor shall be responsible for: 
a. accountability of investigational devices throughout the clinical investigation, 
b. documenting correspondence with all parties involved in the clinical investigation, including 
the Ethics Board/IRB and regulatory authorities 
c. ensuring that the clinical investigation is appropriately monitored by determining the 
extent and nature of monitoring, including the strategy for source data verification, based 
on considerations such as the objective, design, complexity, size, critical data points and 
endpoints of the clinical investigation 
d. reviewing the monitoring report(s) and following up any action(s) required in the 
monitoring report(s) 
e. taking prompt action to secure compliance with all clinical investigation requirements 
f. 
submitting progress reports, including safety summary and deviations, when requested, to 
Ethics Board/IRB and any other regulatory authorities 
 
Clinical investigation close-out 
The sponsor shall: 
a. ensure all clinical investigation close-out activities are properly conducted 
b. provide a statistical analysis of the data 
c. produce a clinical investigation report and submit it for review 
d. ensure that the clinical investigation report, whether for a completed or prematurely 
terminated clinical investigation, is provided to Ethics Board/IRB, participating investigators 
and regulatory authorities, as required by national regulations 
 
Outsourcing of duties and functions 
The sponsor may transfer any or all of the duties and functions related to the clinical 
investigation, including monitoring, to an external organization (such as a CRO or individual 
contractor), but the ultimate responsibility for the quality and integrity of the clinical investigation 
data shall reside with the sponsor. All requirements in ISO 14155 applying to a sponsor shall also 
apply to the external organization inasmuch as this organization assumes the clinical-
investigation-related duties and functions of the sponsor. 
 

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The sponsor shall specify in writing any clinical-investigation-related duty or function assumed by 
the external organization, retaining any clinical-investigation-related duties and functions not 
specifically transferred to, and assumed by, the external organization. 
 
The sponsor shall be responsible for verifying the existence of and adherence to written 
procedures at the external organization. 
 
Communication with regulatory authorities 
The sponsor shall, if required 
a. notify or obtain approval from regulatory authorities in the country where the clinical 
investigation is conducted 
b. report on the progress and status of the clinical investigation 
c. perform safety reporting