Evaluation of Transperineal Biopsy Under Local Anesthesia, a Novel Approach to Decrease Post-Biopsy Infections and Improve Cancer Detection
Phase: NA
Conditions: Infection
Sponsor: Weill Medical College of Cornell University

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title: Randomized controlled trial assessing transperineal prostate biopsy to reduce infection 
complications 
NCT04843566 
Document date: 10/24/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BRANY ID # 18-02-365 
Version/Date: v5.5, 24-OCT-2023 
TITLE:  Randomized controlled trial assessing transperineal prostate biopsy to reduce infection 
complications 
BRANY ID # 18-02-365 VERSION/DATE: v5.5, 24-OCT-2023 
Principal Investigator: 
Jim C. Hu, MD MPH (contact) 
525 E 68th Street, Starr 946 
New York, NY 10065 
Weill Cornell Medicine 
Telephone 646.962.9600 
Fax 646.962.0715 
jch9011@med.cornell.edu 
Edward M. Schaeffer, MD PhD 
NMH/Arkes Family Pavilion Suite 2300 
676 N Saint Clair 
Chicago, IL 60611 
Northwestern University 
Telephone 312.908.8145 e-
schaeffer@northwestern.edu 
Mohamad Allaf, MD 
600 North Wolfe Street, Park 223 
Baltimore, MD 21287 
Johns Hopkins University 
Telephone 410.502.7710 
Fax 410.502.7711 
mallaf@jhmi.edu 
Co-Investigators: 
Behfar Ehdaie, MD MPH 
323 E 68th Street 
New York, NY 10065 
Memorial Sloan Kettering Cancer Center 
Telephone 646.422.4406 
ehdaieb@mskcc.org 
Timothy McClure, MD 
525 E 68th Street, Starr 900 
New York, NY 10065 
Weill Cornell Medicine 
Telephone 646.962.9600 
tim9047@med.cornell.edu 
Anthony Schaeffer, MD 
675 N Saint Clair, Ste 20-150 
Chicago, IL 60611 
Northwestern University 
ajschaeffer@northwestern.edu 
Ashley Ross, MD, PhD 

675 N Saint Clair, Ste 20-150 
Chicago, IL 60611 
Northwestern University 
Telephone 312.695.8146 
ashley.ross@nm.org 
Jeffrey Montgomery, MD 
1500 E Medical Center Dr SPC 5913 
Ann Arbor, MI 48109 
University of Michigan 
Telephone 734.647.8903 
montrose@med.umich.edu 
Arvin George, MD 
1500 E Medical Center Dr, Floor 2 
Ann Arbor, MI 48109 
University of Michigan 
Telephone 734.936.7030 
arvigeor@med.umich.edu 
John Graham, MD 
38 6th Avenue, 2nd Floor 
Brooklyn, NY 11217 
NewYork-Presbyterian Brooklyn Methodist Hospital 
Telephone 718.230.7788 
jng9008@med.cornell.edu 
David Green, MD 
58-42 Main Street 
Flushing, NY 11355 
NewYork-Presbyterian Queens 
Telephone 718.303.3720 
dag9025@nyp.org 
Gerald Wang, MD 
56-45 Main Street 
Flushing, NY 11355 
NewYork-Presbyterian Queens 
Telephone 718.303.3720 
gew9003@nyp.org 
Serge Ginzburg, MD 
1200 Tabor Rd, 3rd Floor 
Philadelphia, PA 19141 
Einstein Urology 
Telephone 215.356.4658 
ginzburs@einstein.edu 
Keith Kowalczyk, MD 
3800 Reservoir Road Northwest, 4th Floor 
Washington, DC 20007 

Georgetown University 
Telephone 202.295.0580 
keith.kowalczyk@medstar.net 
Andres Correa 
333 Cottman Avenue 
Philadelphia, PA 19111 
Fox Chase Cancer Center 
Telephone 215.728.6900 
andres.correa@fccc.edu 
Benjamin Ristau, MD 
263 Farmington Avenue 
Farmington, CT 06030 
University of Connecticut 
Telephone 860.679.4100 
beristau@uchc.edu 
Jonathan Shoag, MD 
11100 Euclid Avenue 
Cleveland, OH 44106 
Case Western University 
Telephone 216.844.3009 
jxs218@case.edu 
Statistician:  
Andrew Vickers, PhD 
485 Lexington Ave 
New York, NY 10017 
Memorial Sloan Kettering Cancer Center 
Telephone 646.888.8233 
vickersa@MSKCC.org Confidentiality 
Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others 
without written authorization from the Principal Investigator. 
 

  
Protocol Summary 
Full Title: 
Randomized controlled trial assessing transperineal prostate 
biopsy to reduce infection complications 
Clinical Phase: 
II 
Principal Investigator: 
Jim C. Hu, M.D., M.P.H. 
Sample Size: 
N= 1,702 
Study Population: 
Men who are aged at least 18 years with: history of Grade Group 
1 or 2 prostate cancer, first diagnosed prior to date of planned 
biopsy (active surveillance cohort); clinical concern for the 
presence of prostate cancer as determined by the treating 
urologist and prior negative prostate biopsy performed ≤36 
months prior to date of planned biopsy (prior negative cohort); 
Men without previous prostate biopsy (first time prostate biopsy) 
Accrual Period: 
Approximately 31 months  
Study Design: 
Prospective, randomized trial with 1:1 ratio to either the 
transperineal or transrectal biopsy group. Participants will be 
assessed for adverse events, pain and discomfort immediately and 
7 days post-biopsy.  
Intervention Description: 
Transrectal prostate biopsy (TR-Bx) under local anesthesia is 
currently the most commonly used approach to evaluate for the 
presence of prostate cancer. A limitation of TR-Bx is the need for 
biopsy needles to pass through the rectal mucosa on their 
trajectory to the prostate, placing men at high risk of an infectious 
complication. An alternative method for performing prostate biopsy 
is via a percutaneous transperineal approach. One limitation of 
transperineal prostate biopsy (TP-Bx) has been the historic need 
for it to be performed under general or spinal anesthesia in order 
for patients to tolerate the multiple required needle passes through 
the perineal skin. Due to recent technical advances TP-Bx may 
now be safely performed under local anesthesia.  
Primary Objective: 
To compare infection adverse events of TP-Bx vs. TR-Bx 
performed under local anesthesia. 
Secondary Objectives: 
To compare other adverse events such as bleeding and urinary 
retention. To compare detection rates of clinically significant and 
insignificant prostate cancer. 
SCHEMA 

 
Table of Contents 
1. STUDY OBJECTIVES ........................................................................................................... 7 
2. BACKGROUND .................................................................................................................... 7 
3. SUBJECT SELECTION ......................................................................................................... 8 
3.1 Study Population ............................................................................................................. 8 
3.2 Inclusion Criteria .............................................................................................................. 8 
3.3 Exclusion Criteria ............................................................................................................. 8 
4. STUDY PROCEDURES ......................................................................................................... 9 
4.1 Study Enrollment and Randomization .................................................................................. 9 
4.2 Data Collection & Confidentiality ....................................................................................... 10 
4.3 Study Calendar ............................................................................................................. 11 
4.4 Antibiotic Administration .................................................................................................. 12 
4.5 Biopsy Procedure .......................................................................................................... 12 
4.6 Duration of Follow Up ..................................................................................................... 12 
5. MEASUREMENT OF OUTCOMES ........................................................................................ 13 
5.1 Adverse events.............................................................................................................. 13 
5.2 Pain, Anxiety and Discomfort ........................................................................................... 14 

5.3 Biopsy Pathology ........................................................................................................... 14 
6. STATISTICAL CONSIDERATIONS ........................................................................................ 15 
 
1. 
Study Objectives 
Primary Objective: The primary objective of this study is to compare the incidence and severity 
of infectious complications between the transperineal and transrectal approaches to prostate 
biopsy. 
Secondary Objectives: Secondary objectives of this study include comparing the incidence of 
other adverse events, associated pain, and cancer detection rates between the transperineal 
and transrectal approaches. 
2. 
Background 
Approximately one million transrectal prostate biopsies (TR-Bx) are performed annually in the 
United States.1 The number of prostate Bx is expected to increase due to the demographic 
growth of the aging male population. Moreover, 44% of U.S. men undergoing initial biopsy 
report having a repeat biopsy within five years.2 Additionally, more than half of men diagnosed 
with prostate cancer currently opt for active surveillance, which requires serial repeat biopsy to 
monitor for disease progression.3 Therefore, biopsy use will only increase with greater adoption 
of active surveillance and the greater number of aging men. The safety and effectiveness of this 
common procedure will impact 1 out of 3 U.S. men at least once during their lifetimes when they 
undergo biopsy.  
Due to the need for biopsy needles to pass through the rectal mucosa on their trajectory to the 
prostate, TR-Bx is associated with a significant risk of infectious complications. The needle 
travels through the “dirty” rectal mucosa to the “clean” prostate at least 12 times,4 and fecal flora 
may seed the vascular prostate gland and bloodstream, leading to infection.5,6 One systematic 
review suggests this rate may be as high as 5%.7  The United States Preventive Services Task 
Force (USPSTF) Grade C recommendation for PSA screening considered adverse events 
associated with biopsy among the harms of PSA-based screening.8 Despite antibiotic 
prophylaxis, 44% of men experience bacteriuria and 16% experience bacteremia after TR-Bx.9  
Furthermore, the risk of post-biopsy infection has increased in recent years due to the growing 
incidence of antibiotic resistance.10 Nam first reported an alarming four-fold, population-based 
increase in post-Bx infection hospital admissions from 0.6% in 1996 to 3.6% in 2005 among  
75,190 patients.11 In particular, men with fluoroquinolone-resistant bacteria in the rectum are at 
increased risk for post-Bx infection and sepsis,12 which can result in dire complications such as 
limb gangrene/amputation, endocarditis, meningitis, disseminated intravascular coagulation 
(DIC) or death.13–18  
As an alternative to the transrectal approach, prostate biopsy may be performed percutaneously 
through the perineal skin. Due to avoidance of the rectum, transperineal prostate biopsy (TP-Bx) 
is associated with an overall lower risk of infectious complications. At some centers, this has 
obviated the need for perioperative antibiotics, which is reinforced by the Society of  
Interventional Radiology Guidelines. 19,20 One additional benefit of TP-Bx is that this procedure 
offers better sampling of the anterior prostate, which is missed with the transrectal approach in 
men with larger prostate volumes due to benign prostatic hyperplasia.21 The biopsy core 
excursion is 2 cm, and therefore sampling of the anterior prostate from the rectum is limited. In 
contrast, the TP approach has relative ease of access to the anterior prostate.6 This is reflected 

in greater detection of clinically significant prostate cancer in retrospective studies with 
transperineal22–25 under general anesthesia (49%-91%) vs. transrectal24,26–31 Bx approaches (14-
42%). Given more than 80% of first-time biopsy nationally are performed without 
MRItargeting,32,33 the utility of in-office transperineal vs. transrectal MRI-targeted biopsy must be 
evaluated as this applies to a large population of men. For instance, the American Urological 
Association professional guidelines were updated to recommend MRI use for first-time biopsy in 
early 2020;34 however, lack of insurance coverage and limited access for urologists to the costly 
MRI-targeted biopsy platform contribute to a large population of men who need to be evaluated 
in the repeat biosy setting of active surveillance and prior negative biopsy.  
Despite the aforementioned benefits of TP-Bx, this procedure has seen limited adoption due to 
the historic need for it to be performed under general anesthesia in order for patients to tolerate 
the required multiple needle sticks to the perineal skin. Additionally, because of the need for 
biopsy needles to traverse the pelvic floor muscles and vascular prostate apex, TP-Bx is 
believed to have a higher risk for urinary retention and bleeding as compared to the traditional 
transrectal approach.  
In recent years, the development of novel local anesthetic techniques and needle guides has 
permitted TP-Bx to be performed in the office setting with a more favorable side-effect 
profile.20,35,36 There has, however, been slow adoption of this procedure by only a handful of 
centers. In fact, national estimates of TP-Bx use place this figure closer to approximately 1-2%.  
In this study, we aim to compare the safety, tolerability, and cancer detection rates of TP-Bx 
versus TR-Bx within the contexts of a randomized clinical trial. The results of this study will 
provide high level medical evidence regarding which method of prostate biopsy carries the best 
risk to benefit ratio for men undergoing evaluation for prostate cancer.   
3. 
Subject Selection 
3.1 Study Population 
This study will include all men who are recommended to undergo prostate biopsy as part of 
routine clinical care. Inclusion and exclusion criteria are listed in the following sections. 
3.2 Inclusion Criteria 
• 
Male sex 
• 
Age ≥18 years 
• 
Active surveillance cohort: History of Grade Group 1 or 2 prostate cancer, first diagnosed  
prior to date of planned biopsy   
• 
Prior negative cohort: Clinical concern for the presence of prostate cancer as determined 
by the treating urologist and prior negative prostate biopsy ≤36 months prior to date of 
planned biopsy 
• 
Men without previous prostate biopsy (first time prostate biopsy) 
• 
Willingness to sign informed consent and adhere to the study protocol 
3.3 Exclusion Criteria  
• 
Acute prostatitis within the last 6 months 
• 
PSA > 20 ng/mL in men who have previously undergone prostate biopsy  
• 
Current non-urologic bacterial infection requiring active treatment with antibiotics 
• 
Unfit to undergo prostate biopsy under local anesthesia  

• 
Prior definitive therapy for prostate cancer, such as radiation therapy or partial gland 
ablation 
• 
Men who have previously undergone prostate biopsy in whom artifact would reduce 
quality of prostate MRI (extensive orthopedic pelvic metal)  
• 
Contraindication to prostate MRI (claustrophobia, pacemaker, chronic kidney disease) in 
men who have previously undergone prostate biopsy 
4. 
Study Procedures 
4.1 Study Enrollment and Randomization 
Eligible patients will be informed of the study by the study urologist and research staff.  
Interested participants may also learn more about the study through online resources such as 
ClinicalTrials.gov or through study informational brochures. All potential subjects will be allowed 
as much time as needed to consider study participation. Patients choosing to participate in the 
study will be consented within the privacy of a clinical exam room. Study staff will explain to 
each potential subject the research objectives, risks and benefits of study participation, and the 
subjects’ rights and responsibilities. For patients who are scheduled for biopsy, electronic 
consent will also be available via phone. Eligible patients will be contacted by a member of the 
study team (i.e. investigator or research coordinator), who will explain the study to the patient. 
The patient will also receive a link to the electronic consent form via email or MyChart message. 
This study will utilize either a traditional one-stage or a two-stage consent process. The reason 
for having the one-stage consent is there are a few sites in which the predominant approach is 
transperineal. Therefore, this two-stage consent does not work. With the one-stage consent,  
patients give permission to participate in the study prior to randomization (tradtional RCT 
consent). With a second-stage consent, subjects who meet all eligibility criteria will sign the 
firststage consent form. Patients will have the option to sign the consent in person or 
electronically. First-stage consent will register the subject to the study and will allow 
investigators to use their data from their medical record and post-biopsy questionnaire 
responses for research purposes. Subjects who sign first-stage consent will be randomized in a 
1:1 ratio to receive TP-Bx or TRBx. The patients’ first-stage consent or their traditional one-
stage consent will be valid for eight months to accommodate for biopsy scheduling. This will 
reduce the number of re-consents and align with the standard of care timeline for biopsy 
procedures. Biopsies are often scheduled as far out eight months from their clinic visit. 
Participants will be consented remotely using an electronic version of the informed consent form 
that follows federal, state, and local regulations, as applicable. We will implement the following 
procedures for electronic informed consent. 
The informed consent document(s) will be sent to the subject or their Legal Authorized 
Representative (LAR), if applicable, via secure email sent by REDCap prior to the scheduled 
consent discussion. The subject or LAR will be asked to review the consent document prior and 
during the consent discussion with a study staff member via phone or approved 
teleconferencing service (i.e., Zoom). The study staff member will confirm the subject or LAR 
has read and has the capacity to appreciate all aspects of the information presented in the 
consent process for the research study. The subject or LAR will be encouraged to ask 
questions. If agreeing to participate, the subject or LAR will sign the consent form using 
electronic informed consent (eConsent) via REDCap. A computer, tablet or touch screen phone 
will be used to capture digital signatures. The person conducting consent will also sign the 
electronic informed consent (eConsent) document in a contemporaneous manner. Subjects will 

be provided with a digital copy of the completed form via email. The informed consent 
discussion and process will be documented by the study team in the subject’s medical record or 
study record. 
If a subject does not have access to a touch screen phone, computer or tablet, cannot work with 
remote electronic informed consent, or the remote electronic informed consent cannot be 
obtained for any other reasons, the consent may be conducted and documented at an in-person 
visit prior to study activities via paper consent form or through REDCap on an ITS tagged 
device. 
The assignment sequence will use randomly permuted blocks of unequal size stratified by 
urologist, PSA (<4, 4-9.9, ≥10 ng / mL) and biopsy indication (prior negative vs. active 
surveillance) and implemented by the randomization model in REDCap, which prevents an 
investigator from learning allocation before a patient is unambiguously registered on study and 
from changing allocation afterwards, thus ensuring full allocation concealment. For men with 
prior biopsy, we exclude men with a PSA >20 ng/mL.  
For the REDCap randomization model, randomization of subjects will occur on the data 
collection form where the randomization field is located. Before a subject is randomized, a 
'Randomize' button will appear next to that field. When a user (who has been given appropriate 
'Randomize' user privileges) clicks that button, a pop-up box will appear that will allow the user 
to randomize the subject. After a subject has been randomized, the grouping (i.e. transrectal or 
transperineal biopsy) will become permanently locked and unmodifiable. The randomization field 
will always be locked and unmodifiable both before and after randomization has occurred for a 
subject.  
Randomization is unblinded, and research coordinators of respective enrolling sites will inform 
their patients of the assigned cohort. 
Subjects randomized to TR-Bx will receive transrectal biopsy. Subjects randomized to TP-Bx will 
undergo a second consent discussion with the enrolling investigator, where the risks and 
benefits of transperineal biopsy will be explained. Subjects can then decide whether to undergo 
standard transrectal biopsy or transperineal biopsy. Subjects who agree to undergo TP-Bx will 
sign the second-stage consent form.  
4.2 Data Collection & Confidentiality 
Study data will be prospectively collected from patient medical records and patient surveys. In 
all participating centers, the site-specific research coordinator will perform baseline data 
acquisition and medical record abstraction. This data will be entered into standardized clinical 
report forms housed within a REDCap environment and hosted by WCM. Each patient will be 
assigned a unique study identifier. 
REDCap (Research Electronic Data Capture) is a secure, web-based application designed 
exclusively to support data capture for research studies. The REDCap platform will be 
partitioned to permit read/write access only to site-specific records such that individual sites will 
be able to access records for their own subjects, exclusively. REDCap has a secure email and 
web-based data collection interface that may be utilized for collecting data. The site-specific 
research coordinator will determine individual patients’ preferred method of survey response 

and may collect survey data either through mail, telephone, REDCap, or during an in-person 
visit. 
Only the WCM research coordinator will be able to review de-identified data across sites to 
conduct data quality checks and share data quality with the study biostatistician.  
To ensure accuracy of data entered in the REDCap database from source documents (including 
surveys and medical record abstract), sites will perform 100% visual review and conduct double 
data entry for a sample (i.e., 10%) of the data. 
Data quality checks will be conducted every 6 months, coinciding with Data Safety and 
Monitoring reviews.  
For protocol deviations fitting immediately reportable criteria, the DSMC’s primary concern lies 
with whether the deviation has the potential to negatively impact subject safety or integrity of 
study data or whether the deviation places subjects at greater risk of harm (including physical, 
psychological, economic or social harm). If the DSMC makes determinations that the reported 
protocol deviation impacts either, it may recommend modifications, suspension or termination of 
the study.    
Interim study findings will be communicated in cases where modifications are recommended. 
The DSMC will require the PI to submit confirmation to the DSMC that the modification(s) have 
been made, or to submit a reason why the PI did not agree with the DSMC’s recommendation. 
4.3 Study Calendar 
 
Month -8 to Day 
0 
Day 0 
Day 5 to 9 
Eligibility  
Xa 
 
 
Informed consent 
X 
 
 
Demographics 
X 
 
 
Medical historyb 
X 
 
 
Physical examc 
X 
 
 
Randomization 
X 
 
 
PSA 
X 
 
 
Rectal swabd 
X 
 
 
Prostate Biopsy 
 
X 
 
Assessment of Adverse Eventse 
 
 
X 
Concomitant Medicationsf 
 
X 
X 

aTo be performed prior to informed consent. bMedical comorbidities, indication for biopsy, 
multiparametric MRI findings, and history of prior biopsy or infection. cHeight and weight. 
dfor transrectal biopsy only. 
eAssessed by patient questionnaire. Events will be grading using Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. fAssessed by patient quaestionnaires. 
4.4 Antibiotic Administration 
For patients undergoing a TR-Bx, antibiotic prophylaxis will be administered in accordance with 
guidelines from the American Urological Association (AUA).37 No antibiotic prophylaxis will be 
administered for patients undergoing a TP-Bx. 
4.5 Biopsy Procedure 
A meeting of study investigators will take place before recruitment to review and ensure 
standardization of biopsies approaches. Investigators will follow the technique described by Kubo 
et al. to administer lidocaine during TP-Bx.20 For both transperineal and transrectal approaches, 
20 mL of 1% lidocaine will be used, respectively, to standardize local anesthesia. At each site, 
however, the choice of commercial MRI-targeted biopsy platform will be left to the physicians’ 
discretion.  
In both transperineal and transrectal biopsy arms for MRI-targeted biopsy, the number of 
systematic biopsy cores will be standardized to 12 cores. The technique for TR-Bx is performed 
as described by Kasivisvanathan et al.22 A total of 12 systematic biopsy cores will be obtained 
from the peripheral zone of the prostate at the base, mid gland, and apex. Locations of the 12 
systematic cores are: Right lateral base, Right lateral midgland, Right lateral apex, Right medial 
base, Right medial midgland, Right medial apex, Left lateral base, Left lateral midgland, Left 
lateral apex, Left medial base, Left medial midgland, and Left medial apex. The technique for 
TPBx is performed as described by Urkmez et al.38. Locations of the systematic cores will be 
obtained as follows: 2 cores each at Right posterior lateral, Right posterior medial, Left posterior 
lateral, and Left posterior medial, as well as 1 core each at Right anterior lateral, Right anterior 
medial, Left anterior lateral, and Left anterior medial. 
In both transperineal and transrectal biopsy arms, the number of targeted biopsy cores will be 
standardized to 3 cores per target, with a maximum of three ROIs permitted to be chosen for 
targeted biopsy. MRI-targeted biopsy registration (i.e., matching of the image of the target on MRI 
with the real-time image of the prostate during biopsy) may be performed by means of visual 
registration or software-assisted registration. 
De-identified video capture of each site’s first 10 TP-Bx and TR-Bx will be distributed for review 
among investigators to monitor for variation in biopsy technique. Deviations from the technique 
that may occur during routine clinical care will be recorded for each case, monitored by the WCM 
DSMC and compared between groups. Research coordinators at each site will randomly select 3 
TP-Bx and 3 TR-Bx for video upload every 3 months. Investigators will review and discuss during 
quarterly video-conferences to ensure consistent procedural fidelity throughout the study. 
4.6 Duration of Follow Up 
Patients will be followed for approximately 7 days following biopsy to evaluate for adverse 
events. Subjects experiencing an adverse event beyond 7 days stabilization will be followed 
until resolution or stabilization. 

5. 
Measurement of Outcomes 
5.1 Adverse events 
The primary objective of this study is to compare the incidence and severity of infectious 
complications experienced by patients undergoing TP-Bx versus TR-Bx. Patients will be 
assessed for complications by way of electronic questionnaire administered 7±2 days post 
biopsy using a REDCap site hosted at Weill Cornell Medical Center. For patients unable to 
complete the questionnaire electronically, responses will be obtained via telephone interview. 
Any patient indicating that they experienced an adverse event will be contacted by the study 
team to seek further details. Additionally, all relevant medical records will be requested. Adverse 
events will be classified in accordance with Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0.  
The primary outcomes are infection rates of TP-Bx versus TR-Bx.  
The secondary outcomes are patient-reported pain and anxiety, and comparison of 
noninfectious complications such as bleeding and urinary retention rates, and cancer detection. 
Timing for assessment of study variables. 
Assessment 
Baseline 
Pre-Bx 
Day 
of Bx 
7-days  
Post-Bx 
Baseline history and physical 
exam, screening, consent 
✓ 
Prior Bx (Y/N) 
✓ 
Prior Bx infection (Y/N) 
✓ 
PSA  
✓ 
Indication for Bx 
✓ 
MpMRI findings 
✓ 
Randomization: TR-Bx vs. TP-Bx 
✓ 
Bx infection risk determination for 
TR-Bx prophylaxis 
✓ 
Bx completed (Y/N) 
✓ 
Bx duration (minutes) 
✓ 
Pain (VAS) 
✓ 
✓ 
Discomfort (VAS) 
✓ 
✓ 
TMI Anxiety (Likert 5 levels) 
✓ 
Decision regret 
✓ 
Adverse events (Y/N) and Bother 
UTI 
✓ 
Sepsis 
✓ 
Urinary retention 
✓ 

Fever 
✓ 
Hematuria 
✓ 
Hematochezia 
✓ 
Hematospermia 
✓ 
UTI diagnosed by HCP 
✓ 
Unplanned HCP contact  
✓ 
Qualitative responses 
✓ 
Bx pathologic outcomes, if cancer: 
✓ 
Gleason grade group(s) 
✓ 
Number of cores positive 
✓ 
Number of cores negative 
✓ 
Maximum cancer core length 
✓ 
Targeted Bx positive (Y/N/NA) 
✓ 
Systematic Bx positive (Y/N) 
✓ 
Location of positive cores 
✓ 
5.2 Pain, Anxiety and Discomfort  
A questionnaire will be given to patients immediately after the biopsy and at 7±2 days post-biopsy 
(Appendix). The questionnaire captures discomfort and pain and fear-anxiety using a numerical 
rating scale (0-10), with higher scores indicating greater intensity of symptoms. The questionnaire 
also asks about the presence or absence of adverse events, with reporting of significant adverse 
events (fever, chills, urinary retention, urinary tract infection, treatment from a doctor) subject to 
follow-up from study staff. 
Infectious complications will be captured as: (1) uncomplicated urinary tract infection (UTI): 
dysuria, urgency, frequency or hematuria without fever and with or without pyuria (>5 white 
blood cells per high-powered field or positive leukocyte esterase on urine dipstick) or bacteriuria 
(≥ 105 colony-forming units/mL); (2) complicated UTI: fever, flank pain, nausea or vomiting with 
or without pyuria and bacteriuria; (3) urosepsis: criteria for sepsis, severe sepsis, and septic 
shock39  were combined and categorized as urosepsis.40  
5.3 Biopsy Pathology 
The proportion of men diagnosed with clinically significant cancer and clinically insignificant 
cancer will be compared by biopsy approach. Detection of prostate cancer will be captured from 
the final pathology report. We will record the prostate cancer grade, number and location of 
positive biopsies for transrectal (location: left vs. right, medial vs. lateral, apex, mid, and base) 
and for transperineal (location: posterior medial, posterior lateral, and anterior), as well as the 
maximum cancer core length (in mm), and total number of negative cores. In order to compare 
outcomes, prostate cancer grade will be categorized into insignificant (Gleason grade group 1) 
and clinically significant (grade group ≥ 2).22  

6. 
Statistical Considerations 
We define infection complication as any of the following: (1) fever requiring medical advice or 
intervention; (2) chills requiring medical advice or intervention; or (3) UTI diagnosed by healthcare 
professional.41 We aim to enroll 1,702 (n=682 active surveillance, n=620 prior negative biopsy, n 
=400 first time biopsy) subjects in this study, with equal randomization between groups. We 
assume that the infection rate in the transperineal group is 0.5%. Given a one-sided α of 0.10, the 
power to reject the null hypothesis of no difference in infection rates will be >80% if the event rate 
in the transrectal group is 2.0%. The event estimate is consistent with published post-transrectal 
biopsy infection rates range from 1% to 17.5%41–49 and the 2017 AUA prostate biopsy guidelines 
cite an infection risk of 5-7%.37 
Analysis of infection, detection of clinically significant cancer (i.e. Grade Group 2+), over-detection 
of clinically insignificant cancer (i.e. Grade Group 1), presence vs. absence of other biopsy related 
complication grade 2 or above and, separately, Grade 1 (patient-reported hematuria, 
hematospermia or hematochezia) will be by logistic regression with site and prior negative vs. 
active surveillance as fixed effect covariates. The Barnard's test will be used to analyze the data. 
Absolute risk differences will be calculated by applying the odds ratio from the regression to the 
prevalence in the transrectal group, with 95% CI obtained by bootstrapping. As a sensitivity 
analysis for high-grade cancers missed on biopsy, we will include as an event any detection of 
grade group ≥2 cancer up to two years after randomization, whether detected by subsequent 
biopsy or upgrading on surgical pathology, as a binary variable. We will also explore whether the 
relative effects of transperineal biopsy on cancer detection varies by race or diagnostic setting 
(active surveillance vs. prior negative) by adding race (African ancestry yes or no) or setting  
(active surveillance vs. prior negative) and the associated interaction terms in two separate 
logistic regression models. 
Rates of missing data are expected to be extremely low because all outcomes are assessed within 
a short period of time after biopsy. Hence, we do not anticipate having to use statistical methods 
to handle missing data. However, if rates of missing data are more than 5%, we will implement 
multiple imputation using chained equations. 
To compare the detection of clinically significant cancer biopsy with systematic vs. MRI-targeted 
biopsy, stratified by transperineal vs. transrectal, the analyses will be conducted separately for the 
prior negative biopsy and active surveillance cohorts separately. For the prior negative biopsy 
patients, we will create a model with the outcome of clinically significant cancer and predictors of 
the linear predictor from the standard Prostate Biopsy Collaborative Group model plus PI-RADS 
version 2 MRI score and MRI prostate volume.50 For the active surveillance cohort, we will use a 
similar approach but use the Canary “base” model for biopsy outcome in active surveillance 
patients.51 We will report the increase in discrimination associated with using MRI volume and 
PIRADS score and conduct decision curve analysis, a decision-analytic technique that weighs the 
value of avoiding unnecessary biopsy compared to missing high-grade cancer, to assess the  
clinical utility of the models.52  
 

  
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APPENDIX 
Immediate post biopsy questionnaire 
Please ask the patient to fill this out after the biopsy, before they leave the department. 
Please check the box corresponding to the number, which describes how you felt 
immediately after the biopsy procedure: 
1. Overall, how much discomfort did the biopsy procedure cause you? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No discomfort 
        Moderate discomfort 
            Extreme discomfort 
2. Overall, how much pain did the biopsy procedure cause you? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No pain 
           Moderate pain 
                     Extreme pain 
3. Overall, how much fear/anxiety did the biopsy procedure cause you? 

0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No fear or anxiety 
   Moderate fear or anxiety 
     Extreme fear or anxiety 
4. Please list any medications that you are currently taking. An example is given in the first 
box: 
Name of 
medication 
Dosage 
Number 
of 
doses per day 
Start Date 
End Date 
Indication 
e.g. ciprofloxacin 
500mg 
2 
09/29/2021 
10/06/2021 
Infection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thank you for completing the questionnaire. Please hand this to the research 7-
day post biopsy questionnaire 
1. Overall, how much discomfort  do you have from the biopsy? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No discomfort 
       Moderate discomfort 
            Extreme discomfort 
2. Do you have pain at the site where the biopsy was taken? 
 
Yes 
No     
 
3. If Yes, how much pain are you having at the biopsy site? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No pain 
        Moderate pain 
       Extreme pain 

Did you experience the following problems during the 7 days after the biopsy procedure? 
 
1. Fevers 
 
 
Yes 
No     
 
5. Blood in the stools (“poop”) 
 
Yes 
No     
 
6. Acute urinary retention, meaning being unable to pass urine (“pee”) which was relieved by 
putting a catheter into the bladder through the penis 
 
Yes 
No     
 
7. Urinary tract infection diagnosed by a healthcare professional (doctor or nurse) 
 
Yes 
No     
 
8. Please list any new medications, especially any painkillers or antibiotics, that you have 
taken since the biopsy. Do not list your regular medications but do list any new medications 
started related to the biopsy. Only list the medications if you have taken them. An example is 
given in the first box: 
Name of medication 
Dosage 
Number of doses per day 
Number of days 
Yes 
No     
2 .Shivering and/or chills, as if you had a flu 
Yes 
No     
3 .Blood in the urine (“pee” ) 
Yes 
No     
4 .Blood in the semen (ejaculate or “cum” ) 

e.g. ciprofloxacin 
500mg 
2 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Since the biopsy, have you had contacts with hospital services for reasons related to the 
biopsy, which were unplanned and not part of the routine study visits? 
Please answer yes if you have had any unplanned contact with any healthcare staff e.g. 
doctor, nurse, other. Please also answer yes if you have had any unplanned consultations 
with healthcare staff over the phone: 
 
Yes 
No     
 
10. Since the biopsy, have you had contacts with the community healthcare team for reasons 
unrelated to the biopsy? 
Please answer yes if you have had any contact with any healthcare staff in the community 
e.g. GP, practice nurse, community nurse, other. Please also answer yes if you have had 
any consultations with community healthcare staff over the phone: 
 
Yes 
No     
 

Thank you for completing the questionnaire. Please contact us if you have any 
questions.