A Prospective, Randomized Trial Comparing Office-based MR-guided Prostate Biopsy Approaches: Transrectal Ultrasound-guided Biopsy Compared With a Transperineal Approach
Phase: NA
Conditions: Prostate Cancer, Elevated PSA
Sponsor: Weill Medical College of Cornell University

 
 
  
 
 
TITLE:  A prospective trial comparing office-based MR-guided prostate biopsy approaches: 
transrectal biopsy compared with a transperineal approach 
 
IRB Protocol #: 1705018187 
 
NCT #: NCT03632655 
 
 
Version Date: 05Nov2018 
 
Principal Investigator: 
 
Jim C. Hu 
525 E 68th Street, Starr 900 
212-746-4600 
 
 
jch9011@med.cornell.edu 
 
 
Participating Sites:  Weill Cornell Medicine  

Protocol v.1, incorporating Amendment 3.0 
Version Date 05Nov2018 
 
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 WCM. 

Protocol v.1, incorporating Amendment 3.0 
Version Date 05Nov2018 
 
 
List of Abbreviations 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSC 
Clinical Translational Science Center  
DSMB 
Data Safety Monitoring Board 
DSMP 
DRE 
Data Safety Monitoring Plan 
Digital Rectal Examination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
MR 
Institutional Review Board 
Magnetic Resonance 
PHI 
Protected Health Information 
PI 
PSA 
Principal Investigator 
Prostate Specific Antigen 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SUSAR 
TP-Bx 
TR-Bx 
Suspected Unexpected Serious Adverse Reaction  
Transperineal biopsy 
Transrectal biopsy 
UAP 
Unanticipated Problem 
WCM 
Weill Cornell Medicine 

 
 
  
 
Protocol Summary 
 
Full Title:  
 
 
 
A prospective trial comparing office-based MR-guided prostate 
biopsy approaches: transrectal biopsy compared with a 
transperineal approach 
Principal Investigator:  
Jim C. Hu 
Sample Size: 
 
N= 1,500 men 
Study Population: 
 
Men >18 years of age with suspicion for prostate cancer based 
upon an elevated PSA or abnormal digital rectal examination. Men 
who have had prior prostate biopsies and men on active 
surveillance are eligible for inclusion. 
Study Design: 
 
The purpose of the study is to compare the safety and efficacy of 
transperineal biopsy versus transrectal biopsy performed in the 
outpatient setting. 
Study Duration: 
 
6 months 
Primary Objective:  
To compare infection rates, uro-sepsis hospitalizations, and 
patient-reported pain of in-office transperineal versus transrectal 
biopsy. 
Secondary Objectives: 
To gather outcomes including adverse events such as bleeding 
and urinary retention. To compare detection of clinically significant 
and insignificant prostate cancer. 

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1. 
Study Objectives 
 
1.1 Primary Objectives  
The primary objective of this study is to compare infection rates, uro-sepsis 
hospitalizations, and patient-reported pain of in-office transperineal versus transrectal 
biopsy. We will be using the data from the biopsy pathology report (standard of care)--no 
additional biopsy specimen will be collected. 
1.2 Secondary Objectives 
 
Secondary outcomes include other adverse events such as bleeding and urinary 
retention, which will be categorized and compared with Common Terminology Criteria for 
Adverse Events (CTCAE). Additionally, we will compare detection of clinically significant 
and insignificant prostate cancer. 
 
2. 
Background 
2.1 Study Design 
The feasibility of outpatient transperineal biopsy (TP-Bx) has been well 
demonstrated.(Bianco & Martínez-Salamanca, 2016; Merrick et al., 2016; Smith et al., 2014) 
New technology now allows for fusion of MRI images with TP devices, allowing for targeting 
of cancerous-appearing lesions on MRI. Such technology that fuses MRI-imaging with 
transrectal biopsy (TR-Bx) has become routine in U.S. clinical practice, with improved 
cancer detection rates as compared with standard TRUS.(Ahmed et al., 2017; Robertson, 
Emberton, & Moore, 2013) Our randomized trial will compare the safety and efficacy of TP-
Bx versus TR-Bx performed in the outpatient setting.  
 
The primary objective of this study is to compare infection rates, uro-sepsis hospitalizations, 
and patient-reported pain of in-office transperineal versus transrectal biopsy. 
Secondary outcomes include other adverse events such as bleeding and urinary retention, 
which will be categorized and compared with Common Terminology Criteria for Adverse 
Events (CTCAE). Additionally, we will compare detection of clinically significant and 
insignificant prostate cancer. 
 
ARM 1: 
Men will be randomized to receiving either TP or TR targeted biopsy. We will use block 
randomization by date, assigned by using www.random.org (Odd will be TP, even will be 
TR). Lesions with PI-RADS >=3 will be targeted with 1 biopsy for every 3 mm in size, and 
then a standard template will be performed. All men will receive a urine culture within 2 
weeks of biopsy and will be started on antibiotic prophylaxis prior to biopsy in accordance 
with AUA antimicrobial prophylaxis guidelines. (AUA 2016) Men with a positive urine culture 
will be treated with culture-specific antibiotics and must have a documented negative urine 
culture prior to biopsy.  
 
ARM 2: 
Men will receive a TP targeted biopsy, followed by a TR targeted biopsy on a single 
procedure date. All men will receive a urine culture within 2 weeks of biopsy and will be 
started on antibiotic prophylaxis prior to biopsy in accordance with AUA antimicrobial 
prophylaxis guidelines. (AUA 2016) Men with a positive urine culture will be treated with 
culture-specific antibiotics and must have a documented negative urine culture prior to 
biopsy. 
 

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Our hypothesis is that TP-Bx is less painful, has lower infection rates, and results in fewer 
adverse events than TR-Bx, with similar cancer detection rates. 
 
2.2 Rationale and Justification 
Interest in transperineal prostate biopsy (TP-Bx), as compared to transrectal biopsy (TR-Bx), 
has increased in recent years.  
 
TR-Bx, either performed with fusion of MRI-imaging or as a standard template, is the current 
standard of care for prostate cancer detection in the United States. The infectious risks 
associated with TR-Bx have increased over the past decade, likely due to increased 
microbial resistance and widely varying prophylactic regiments (Borghesi et al., 2017)  
 
TP-Bx, performed through the perineum and avoiding the rectal mucosa, minimizes 
transmission of the rectal flora to the prostate and may result in lower infectious 
complications than TR-Bx. These infectious complications, which include bacteremia and 
sepsis, can result in lengthy and costly hospitalizations. (Anastasiadis, van der Meulen, & 
Emberton, 2015)  
 
Furthermore, given anatomic considerations when performing TR-Bx, the anterior and apical 
regions of the prostate are often under sampled unless specifically targeted. (Numao et al., 
2012; Volkin et al., 2014) TP-Bx offers an additional advantage of easier access to these 
regions within the prostate and may improve cancer detection in these areas. 
 
2.3 Risk/Benefit Assessment  
The risks associated with this study are no greater than the current standard of care TRUS 
biopsy performed for the diagnosis of prostate cancer. To our knowledge, there are 
comparable risks of discomfort associated with TR and TP biopsy. Both procedures may 
miss clinically-significant prostate cancer, though this is a known limitation of prostate 
sampling. 
 
Patients with elevated PSA, abnormal digital rectal examination and concerning findings on 
MRI will receive a targeted prostate biopsy, which may improve the detection of clinically 
significant cancer as compared with standard template TR. TP biopsy may be associated 
with lower risk of infection though this remains to be demonstrated. 
 
3. 
Subject Selection 
 
3.1 Study Population 
Men diagnosed with prostate cancer who meet the inclusion and exclusion criteria listed 
below will be eligible for participation in this study. 
 
3.2 Inclusion Criteria 
1. Men aged >18 years with suspicion for prostate cancer based upon an elevated PSA 
or abnormal DRE; or 
2. Men who have had prior prostate biopsies; or 
3. Men on active surveillance 
 
3.3 Exclusion Criteria  
1. Men with active urinary tract infection; or 
2. Metastatic prostate cancer; or 

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3. History of colorectal surgery limiting insertion of transrectal probe; or 
4. Evidence of acute or chronic prostatitis; or 
5. Concern for perineal cellulitis or fistula 
 
4. 
Registration Procedures 
 
4.1 Patient Registration 
Patients will be centrally registered with the Office of Billing Compliance. To register a 
patient, submit the following documents via the JIRA Registration Process:  
 
• 
Legible copy of the HRBAF 
• 
First and last page of signed informed consent form  
 
Registration must be completed within 24 hours of the signing of informed consent.  
 
5. 
Study Procedures 
Men will be randomized to receiving either TPM or TRUS targeted biopsy. Lesions with 
PI-RADS ≥3 will be targeted with 1 biopsy for every 3 mm in size, and then a standard 
template will be performed. All men will receive a urine culture within 2 weeks of biopsy 
and will be started on antibiotic prophylaxis prior to biopsy in accordance with AUA 
antimicrobial prophylaxis guidelines. (AUA 2016) Men with a positive urine culture will be 
treated with culture-specific antibiotics and must have a documented negative urine 
culture prior to biopsy.  
 
5.1 Duration of Therapy and Criteria for Removal from Study 
 
Subjects will be followed through their prostate cancer treatment. 
 
5.2 Duration of Follow Up 
 
 
Subject follow-up period is approximately 6 months. 
 
6. 
Statistical Considerations 
The study will be designed as an equivalence trial with an alpha of 0.05, power of 80%, 
SD of 1.6, and equivalence limit of 1 point. This suggests a sample size of 440 per arm, 
for which we would add 10% for dropout, thus 500 patients per arm. 
 
6.1 Study Design/Endpoints; Sample Size/Accrual Rate 
Given the prospective nature, there will be a continuously accruing series to end on 
01/10/2020; we hope to accrue 1,500 patients through that time. 
 
6.2 Analysis of Endpoints 
We will perform statistical analyses using SPSS and Stata software. Specifically, we will 
create frequency tables to evaluate the distributions of dichotomous and categorical 
outcomes with predictor variables. We will compare dichotomous outcomes using chi-
square tests or Fisher exact tests. For continuous variables, means, medians, and 
standard deviations will be computed and compared utilizing t-tests for normally 
distributed variables and Wilcoxon signed rank sum tests for not normally distributed 
variables. 
 
7. Adverse Event Reporting Requirements  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 

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investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the 
safe use of the drug or device under investigation.  Safety will be monitored by evaluation of 
adverse events reported by patients or observed by investigators or research staff, as well 
as by other investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
7.1 Adverse Event Definition 
An adverse event (also referred to as an adverse experience) can be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug, and does not imply any 
judgment about causality. An adverse event can arise with any use of the drug (e.g., 
off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose.  
 
 
 
 
7.1.1 Investigational Agent or Device Risks  
 Focal therapy risks include bleeding, infection, injury to 
urethra/bowel/bladder, pan, and less commonly, fistula or osteomyelitis.  
 
 
7.1.2 Adverse Event Characteristics and Related Attributions 
 
 
We will utilize the CTCAE classification system to categorize AEs. 
 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
 
7.1.3    Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE 
log will be maintained by the research staff and kept in the patient’s 
research chart.    
 
 
 
7.1.4   Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the 
IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immedi
ate_Reporting_Policy.pdf.  
 
7.2 Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, 
congenital anomalies and any other serious events that may jeopardize the 
subject or require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (Modify as necessary) 
 

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7.2.1 Reporting of SAE to IRB 
All SAEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:   
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immedi
ate_Reporting_Policy.pdf.  
 
 
 
7.2.2 Reporting of SAE to FDA 
If an SAE occurs on this study, the event will be filed on a MedWatch 
form with the FDA. The investigator must notify the FDA of any SAE’s as 
soon as possible but no later than 7 calendar days after the initial receipt 
of the information. 
 
Food and Drug Administration 
Center for Devices and Radiological Health 
MDR Policy Branch 
10903 New Hampshire Avenue 
WO Bldg. 66, Room 3217 
Silver Spring, MD 20993-0002 
 
7.3 AE/SAE Follow Up 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the 
patient discontinues participation from the study.  
 
 
8.  
Data and Safety Monitoring Plan (DSMP) 
The attending physician will monitor the subject in real time during the procedure. All 
men will receive a urine culture within 2 weeks of biopsy and will be started on antibiotic 
prophylaxis prior to biopsy in accordance with AUA antimicrobial prophylaxis guidelines. 
(AUA 2016) Men with a positive urine culture will be treated with culture-specific 
antibiotics and must have a documented negative urine culture prior to biopsy.  
 
The risks associated with this study are no greater than the current standard of care TR 
biopsy performed for the diagnosis of prostate cancer.  Subject safety will be assessed 
in real-time by physician. Any AEs or SAEs that occur will be reported to the WCM IRB.