Randomized-controlled Trial: Whether Transperineal Prostate Biopsy Under Local-anaesthesia Using a Transperineal-access System is Non-inferior to Standard Transrectal Biopsy to Detect Prostate Cancer in Biopsy-naïve Men
Phase: NA
Conditions: Prostate Cancer, Prostatic Hyperplasia
Sponsor: The University of Hong Kong

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STUDY PROTOCOL 
 
 
Title: 
 
Randomized-controlled trial: whether transperineal prostate biopsy under local-
anaesthesia using a transperineal-access system is superior to standard transrectal 
biopsy to detect prostate cancer in biopsy-naïve men 
 
 
Principle Investigator: 
 
Dr Wayne Lam 
BSc(Hons) MBBS(Lond) LMCHK MSc(Urol) FRCSEd(Urol) 
 
 
Co-Investigators: 
 
Dr Brian Ho 
MBBS(HK) FRCSEd(Urol) FCSHK FHKAM 
 
Dr Wai-Kit Ma 
MBChB(CUHK) FRCSEd(Urol) FCSHK FHKAM 
 
Dr Vince Vardhanabhuti 
BSc(Hons) MBBS FRCR 
 
Dr James Tsu 
MBBS(HK) FRCSEd(Urol) FCSHK FHKAM 
 
 
Correspondence: 
Dr Wayne Lam 
Assistant Professor in Urology 
4/F, K Block, Division of Urology, Department of Surgery 
Queen Mary Hospital, Hong Kong 
Waynelam.urology@gmail.com 
 
 

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Introduction 
 
The incidence of prostate cancer (PCa) has increased considerably in recent years 
[1, 2]. The reported lifetime risk for men in Hong Kong to be diagnosed with PCa is 1 
in 31 before the age of 75, and is currently the third commonest cancer Hong Kong 
men according to the Hong Kong Cancer Registry [3]. This highlights the importance 
of thorough and fundamentally a safe investigation technique to correctly identify 
patients with PCa. Such test should be able to sensitively detect PCa, and provide 
early diagnosis. Critically, such test is required to provide accurate disease risk 
stratification, which is absolutely crucial in guiding level of appropriate treatment is 
necessary in patients diagnosed with PCa. 
 
According to recommendations from the National Institute for Health and Care 
Excellence (NICE) guidelines, current standard clinical practice considers 
histological diagnosis of PCa a necessity in majority of patients presented with 
localized disease who are eligible for treatment [4]. This, alongside with prostate 
specific antigen (PSA) level, digital rectal examination (DRE) findings, and 
increasingly the use of multi-parametric MRI (mpMRI) imaging, collectively allows 
risk stratification of PCa.  
 
The current pathway to obtain prostate tissue for histological diagnosis of CaP is by 
transrectal ultrasound-guided systematic biopsy (TRUSB) of the prostate, usually 
following the detection of a raised serum PSA level and/or suspicious rectal 
examination findings. TRUSB has been the standard prostate tissue sampling 
technique for men suspected with PCa for over 30 years. It is an office-based 
procedure carried out under local anaesthesia (LA), with 10 to 12 biopsy cores 
directed towards the lateral peripheral zones of the prostate thought to harbour 
majority of cancers [7]. However, there are still various well-known cancer detection 
limitations and patient safety problems associated with TRUSB. 
 
Firstly, a very significant portion of tumours are being missed with the TRUSB 
technique [8]. It has been well- known that over 30% of patients with low risk PCa on 
TRUSB have been found to harbour clinically significant PCa [9]. Many of these 
tumours missed on TRUSB are located in the anterior and apical regions of the 
prostate, which TRUSB is difficult to access, in particular in patients with a large 
prostate volume 
 
Secondly, TRUSB requires the biopsy needle to penetrate through the bowel 
(rectum). This results in high risk of developing sepsis following biopsy, despite all 
patients undergoing the procedure being started on antibiotics prophylactically. This 
is a serious complication which can potentially be life-threatening. Our previous 
study has already demonstrated a high prevalence of fluoroquinolone-resistant and 
ESBL-producing rectal flora in our local population in Hong Kong [10]. The risk of 
developing post-biopsy sepsis in Hong Kong is high. 
Transperineal prostate biopsy (TPB) has been developed to provide a more 
comprehensive biopsy method to improve cancer detection rate by directing biopsy 
cores through the perineal skin. Theoretically, TPB enables access to sample the 
entire prostate, in particular the anterior and apical regions which are not easily 
accessible through the standard TRUSB method. By sampling the prostate using 

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biopsy needles directly inserted through the perineal skin rather than bowel, the risk 
of sepsis is reduced. However, this technique requires multiple needles traversing 
through the perineum, and requires to be carried out under general anaesthesia 
(GA). Another disadvantage is a stabilising stepping unit is required to provide a 
consistent alignment of the ultrasound probe against the prostate in order to carry 
out the biopsies. Such stabilising stepping units are costly. 
A novel but simple transperineal access system device known as PrecisionPoint 
(Perineologic, Cumberland, MD, USA) has been developed to tackle the 
aforementioned limitations of TPB. This revolutionary device utilises a single access 
needle cannula mounted directly on to the ultrasound probe, which acts as an 
access point traversing through the perineal skin. This design minimises the number 
of needle punctures through the skin, enabling TPB to be carried out under LA. A 
stabilising stepping unit is not required with this technique. The device has gained 
the United States Food and Drug Administration (FDA) approval [11], and results 
from small contemporary series have already been published with very promising 
results in terms of cancer detection rate and safety [12]. 
TRUSB has a poor cancer detection rate and is associated with potentially fatal 
septic risk. TPB, if able to be carried out under LA as an office-based procedure, can 
potentially provide a better cancer detection rate with significantly reduced sepsis 
risk. It has fundamentally a very high potential to become the new gold standard in 
obtaining prostate tissue for histological diagnosis of PCa.  
With an increasing number of men in Hong Kong with elevated serum PSA suspicion 
of PCa needing prostate biopsy, we strongly feel that it is fundamental to carry out a 
study to determine the most effective, safe and tolerable prostate biopsy technique 
which fits with the clinical practice in Hong Kong. 
 
 
 
 
 

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Aim of study 
 
To evaluate whether TPB using a noval transperineal access system under LA is 
superior to standard 12-cores TRUSB in detecting prostate cancer (PCa), in patients 
with clinical suspicion of PCa with no prior prostate biopsy.  
 
Other objectives of the study include: 
 To assess whether LA TPB has reduced post-biopsy sepsis rate 
 To assess whether patient tolerability with LA TPB is non-inferior to standard 
TRUSB 
 
 
Study design and method 
 
All patients referred with a raised serum PSA or abnormal DRE will be seen in the 
urology specialist unit outpatient clinic (OPD), where patients will be screened and 
assessed for eligibility for the study. All patients must satisfy all inclusion criteria and 
none of the exclusion criteria outlined in the table below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If eligible, informed consent will be obtained. Baseline characteristics will be 
recorded, such as age, height, weight, allergies, past medical history, family history 
of PCa, drug history, presenting PSA and DRE findings. Baseline urine and blood 
samples will be taken. Baseline IPSS, EQ-5D-5L and IIEF questionnaires will be 
filled by each participant. Eligible patients will be randomized to either the LA TRUSB 
arm or the LA TPB arm. Randomisation will be executed per participant with a third-
party statistical software using a computer-generated randomization tool, following 
completion of informed consent procedure. Equal allocation between both arms will 
be performed, using random permuted blocks of varying size. In order to ensure 
allocation concealment, block sizes will not be disclosed and randomisation codes 
will be obtained through a web-based application. 
 
Procedures will be carried out within 30-60 days following first visit. Procedure in 
each arm will be carried out according to protocols described below within 60 days of 
randomisation. All patients on anticoagulants will be advised to stop 7 days prior to 
biopsy. 
Inclusion criteria 
Exclusion criteria 
1. Patients between ages 40 – 
80  
1. Patients who are unable to 
provide written informed 
consent 
2. Serum PSA 20ng/mL 
2. Known history of prostate 
cancer 
3. Suspected tumour clinical 
stage T2 on DRE 
3. Contraindication to prostate 
biopsy 
4. No previous history 
prostate biopsy 
4. Had pre-biopsy mpMRI 
5.  Medically fit to undergo 
procedures according to 
study protocol 
5. Rectal abnormality precluding 
transrectal ultrasound 

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For the superiority hypothesis, based on assumptions from results from previous 
preliminary studies, a sample size of 330 subjects (165 per group) will achieve 80% 
power to detect superiority of LA TPB over TRUSB.  The calculation used a one-
sided Z test assuming superiority margin of 10% and the significance level at 0.05. 
Estimating up to 10% of patients will withdraw from the study or loss to follow-up, 
364 patients will need to be recruited for the study (182 patients per arm). 
 
Patient recruitment and enrollment will take place at urology outpatient clinics at a 
tertiary university teaching hospital. In 2017, on average 16 biopsy-naïve men with 
raised serum PSA underwent TRUSB per month. It is therefore estimated that the 
study will complete within 26 months of commencement. The start date of the study 
will be 1st April 2019, and the estimated completion date for recruitment will be 1st 
June 2021. 
 
 
Statistical analysis 
 
Primary outcome analysis will be based on intention to treat sample as well as per 
protocol sample. 
 
Primary endpoint is difference in proportion of patients with PCa detected between 
the two cohorts based on histopathological analysis. Absolute differences in PCa 
detection rate will be calculated with 95% CIs. If lower bound of 97.5% CI for the 
difference in cancer detection rates of LA TP biopsy compared with TRUS biopsy is 
greater than -5%, then TP biopsy will be deemed non-inferior. If lower bound is 
greater than 0, TP will be deemed superior. Comparisons will be made concerning 
the basic characteristics between the two arms of participants. If any imbalance were 
identified, a multivariable logistic regression analysis will be carried out, with clinically 
significant PCa as the dependent variable and group as the independent variable. 
Any baseline characteristics imbalance will be used as a covariate. 
 
Effect sizes concerning secondary outcomes will be presented with 95% CIs. For 
binary outcomes, differences between the two arms will be calculated with 95% CIs. 
Any imbalance between the two arms will again be accounted for with a multivariable 
logistic regression analysis. For continuous outcomes, mean differences in outcomes 
between the two study arms will be calculated with 95% CIs. Imbalances identified 
between the two groups will be accounted for in a multivariable linear regression 
analysis. Non-parametric test will be used if any secondary outcomes were found not 
normally distributed. All statistical analysis will be carried out using the SPSS 
software. 
 
 
Primary end-point 
 
Primary outcome is proportion of participants identified with PCa, assessed on a per 
patient basis from each individual’s biopsy histopathological analysis report (i.e. 
comparison of absolute cancer detection rate). Definition of PCa is presence of any 
PCa regardless of grade on histopathology. Definition of clinically significant PCa is 
any core containing Gleason grade 3+4 disease or above. Timeframe for 

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assessment will be when histopathology reports are available, usually expected to 
be within 14 days following biopsy procedures. 
 
 
Secondary end-points 
 
Secondary outcomes, tools for assessment, and their corresponding timeframe for 
assessment are summarized in table below. 
 
Secondary outcomes 
Assessment tool 
(if applicable) 
Timeframe for 
assessment 
Procedure tolerability 
Visual Analogue 
Scale (VAS) 
Immediately following 
test 
Health-related quality of 
life and patient 
satisfaction 
EQ-5D-5L 
questionnaire, 
IPSS, IIEF  
Baseline, 24 hours post-
biopsy, and 30 days 
post-biopsy 
Proportion of men 
developing sepsis  
Either: 
1) admission to 
hospital for 
urosepsis; or 
2) Presence of 
nitrites in urine at 
<1 month 
1 week to 30 days post-
biopsy 
Detection rates of 
patients with clinically 
significant PCa (Gleason 
3+4 or higher) 
Histopathology 
report 
When histopathology 
results available, 
expected to be within 14 
days following biopsy 
Maximum cancer core 
length (MCCL, mm) 
Histopathology 
report 
When histopathology 
results available, 
expected to be within 14 
days following biopsy 
Proportion of men go on 
to undergo definitive 
curative treatment for 
local disease (including 
surgery and 
radiotherapy) 
Clinical records, 
patient interview 
After treatment 
decision, expected to be 
within 30 days following 
biopsy 
Procedure times 
(minutes) 
Time from start of 
ultrasound probe 
insertion to probe 
removal 
During test 
Cost per diagnosis of 
cancer (HKD) 
 
30 days post-biopsy 
 
 
 
 
 
 
 
 

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Data Access and Handling 
 
To protect patient privacy, all research data will be handled in line with Hospital 
Authority’s or Hospital’s policy in handling/storage/destruction of patients’ medical 
records. They would be locked in cabinets where the department/ward keep patients’ 
medical records. Electronic data would be saved in secured computer of the hospital 
with restricted access. USB Device would not be used for patient information for 
personal data.  
 
Personal data (name, HKID, address and any other personal identifiable information) 
will not be recorded on the projects’ data sheets or electronic files. A study code will 
be used.  
Any documents or electronic files containing personal identifiable information would 
be considered as part of the medical record and will be dealt with the same stringent 
regulations of security according to the hospital policies. The principal 
investigator/co-investigator will be responsible for the execution of data  
protection.  
 
This study will fully comply with the requirements of ICH-GCP.  
 
 
 
 

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Ethics  
 
There is no conflict of interest in this study.  
 
 
Financing and Insurance  
 
A grant has been applied (HMRF) to help funding in the purchase of required 
equipments to carry out this study. No additional insurance requirements will be 
necessary.  
 
 
 

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References: 
 
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10. Tsu J, Ma W, Chan W, et al. Prevalence and predictive factors of harbouring 
fluroquinolone-resistant and extended-spectrum b-lactamase-producing rectal 
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prostate biopsy. Urology 2015;81:15-21. 
 

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11. United States Food and Drug Adminstration Approval of PrecisionPoint 
Transperineal Access System. 
www.accessdata.fda.gov/cdrh_docs/pdf16/k160414.pdf 
 
12. Meyer A, Joice G, Schwen Z, Partin A, Allaf M, Gorin M. Initial experience 
performing in-office ultrasound-guided transperineal prostate biopsy under 
local anesthesia using the PrecisionPoint Transperineal Access System. 
Urology 2018, https://doi.org/10.1016/j.urology.2018.01.021