2.1 Study population and setting
Prospective recruitment of men referred with suspected clinically localised PCa will be carried out in urology clinics. The number of patients screened for eligibility over the recruitment period is estimated to be 1000. The number of patients not eligible for the study is estimated to be 350 and the number of patients who are likely to decline is estimated to be 50. The number of participants who are likely to progress to pre-biopsy MRI is estimated to be 600. Local audit information suggests that after a positive diagnosis of PCa, around 25% of men will opt for radical surgery. Based on the recruitment of 600 eligible men, the lowest amount of complete data for radical prostatectomy histology for analysis will be n~150. Our power calculation based on 80% sensitivity and a precision of +/- 9% and an AUROC = 0.9 suggests that we need a minimum of 80 men with complete datasets from imaging and histopathology of radical prostatectomy to answer the primary objective. The dropout rate and incomplete datasets have been taken into consideration in designing this study.
Rais-Bahrami et al.8 suggest that 80% of all pre-biopsy MRI (n~600) will have lesions suspicious of PCa, regardless of the level of suspicion assigned by mpMRI (n~480). Based on such information, we calculated that each of the two randomisation arms will have approximately (n~240) patients.
Initially, the total duration of the recruitment phase was 48 months; however, this will now be extended to 66 months with approval from the funding body. It is estimated that approximately 600 participants will be recruited and will receive a pre-biopsy MRI scan.
Participants will then be divided into two groups based on the mpMRI results. The group with positive mpMRI (n~480) will be randomised to the intervention (TRUS and MRI/US fusion-guided biopsy) group (n~240) or the standard care (TRUS-guided biopsy) group (n~240). The group with negative mpMRI (n~120) will undergo standard care (TRUS-guided biopsy) with histological comparative analysis. Participants will be followed through to a definite treatment stage. At sites where local facilities allow and for those who will undergo radical prostatectomy, histological findings will be compared to the pre-biopsy MRI (n~80). The active trial participation for each participant will be varied depending on sites’ local pathway.
Initially, the total duration of the recruitment phase was 48 months; however, this will now be extended to 66 months with approval from the funding body. It is estimated that approximately 600 participants will be recruited and will receive a pre-biopsy MRI scan.
2.2 Participant selection and enrolment
As standard care pathways differ among sites, the route of identification and screening of eligibility will differ in order to accommodate the local pathway. Potential participants will be identified by either the clinical team or the study team, with Caldicott Guardian Approval, depending on local practice.
2.2.1 Identifying potential participants
Potential participants may be identified through the following routes:
- At the urology clinic
- From GP referrals to the urology team
- By the urology team after standard care mpMRI (positive results only)
2.2.2 Contacting potential participants
Contact will be made by either the clinical team or the study team through the following routes:
The clinical team will assess whether the patient meets the eligibility criteria for the study. If so, the study patient information sheet (PIS) will be given and a contact telephone number will be requested for a follow-up phone call. A model PIS is shown in supplementary appendix 1.
The clinical urological team will review GP referral letters or positive mpMRI results and identify patients who meet trial eligibility criteria. Those who met the eligibility criteria will be sent a clinic appointment with the trial information leaflet.
The clinical urological team or delegate may contact the patient and check whether he has received his NHS clinic appointment before sending out the information pack. After confirmation of receipt, the urological team or delegate (with appropriate Caldicott Guardian Approval) will introduce the study to the patient and if they indicate interest, then an invitation pack will be sent.
If the patient declines the information pack or declines to provide a telephone number, no further attempt to recruit the patient will be made. The clinical or trial team will telephone patients who have agreed to be contacted. Any questions will be answered, and the patient will be asked whether he is interested in participating. The research team will arrange to see the patient for consent discussion. If required, the patient will be given additional time to consider participation before a final decision is made to arrange an appointment.
Patients will be advised to attend all their planned scheduled appointments in the invitation letter and study introduction call. Prospective participants will be encouraged to telephone if they have any questions that they would like answered prior to attendance or to inform the research team if they change their minds with regard to participating. Patients who do not wish to participate will follow their local standard of care pathway.
2.2.3 Inclusion criteria
- Males aged 40–75 years at referral
- Have an MRI scan in the past: for sites with pre-biopsy MRI included in standard of care
- With at least 10 years’ life expectancy at clinical referral
- With clinically localised PCa: PSA ≤20ng/ml
- And/or abnormal DRE but < T3 disease
- Ability to give informed consent
2.2.4 Exclusion criteria
- Unable to give informed consent
- Prior prostatic biopsy within 12 months
- Contraindications to biopsy
- Poor general health and life expectancy < 10 years
- Previous diagnosis of acute prostatitis within 12 months
- History of PCa
- Prior transurethral prostatectomy
- Contraindications to MRI including: cardiac pacemakers, allergic reaction to gadolinium-based contrast, renal failure, intracranial clips, claustrophobia (applicable to participants who do not receive MRI as part of standard care pathway)
- Previous hip replacement (applicable to participants who do not receive MRI as part of standard care pathway)
2.2.5Ineligible and non-recruited participants
Ineligible patients or those who decide not to enter the study will receive standard of care. The reason(s) for ineligibility will be explained to all individuals who express interest in the study. Any questions that they have will be answered. A record of the number of patients screened will be kept that indicates the number of patients eligible/ineligible to participate.
2.2.6 Blinding
In this study, the blinding of the biopsy performer on men randomised to MR/US fusion-guided biopsy is not feasible, but radiologists and pathologists will be double blinded regarding to the patients’ outcomes until the end of the statistic analyses.
2.3 Allocations and Interventions
All enrolled participants will be offered 1.5 Tesla or 3.0 Tesla mpMRI prior to prostate biopsy where this is not already within the standard care pathway. A subgroup of participants with positive pre-biopsy MRI will be randomised into two further subgroups at a 1:1 ratio. Randomisation will be via TRUST, a web-based, good clinic practice (GCP) - compliant randomisation system run by the HIC. Randomisation will be implemented with random block sizes stratified by site and minimised by: The Prostate Imaging Reporting and Data System (PI-RADS) suspicion score (3, 4 or 5); index lesion size (in two categories: above and below 6mm in maximal diameter on MRI); age (40–59, 60–75); PSA <10.1 or ≥10.1 to ≤20ng/ml). The first will undergo an TRUS and MRI/US fusion-guided biopsy and the second will undergo standard of care TRUS-guide biopsies only. The MRI/US fusion-guided biopsy will be performed during the same attendance as the TRUS-guided biopsy. TRUS and MRI/US fusion-guided biopsies will be performed by NHS-accredited radiologists and/or urologists from the research team. The persons undertaking the biopsy will have prior experience and will have received appropriate training from clinical experts and/or the equipment supplier’s application specialist(s). Those participants with negative pre-biopsy MRI will follow the local standard of care pathway; where this includes biopsy, data from the biopsy will be collected for analysis.
In a subgroup of patients who undergo radical prostatectomy the prostatectomy specimen will be sectioned using customised molds9, 10 allowing for direct comparison with mpMRI. This will be carried out in NHS Tayside, NHS Grampian and other sites where local facilities allow. Comparison of mpMRI with a reference standard of radical prostatectomy pathology will be performed as the primary outcome.
2.4 Withdrawal procedures
It will be made clear to patients that they can withdraw from the study at any time and return to standard of care. however, any data collected up to the time of withdrawal will be included if participants agree to it.
2.5 Proposed outcome and statistical analyses
2.5.1 Prediction Performance (Objective 1)
The diagnostic accuracy of each of the three mpMRI predictive variables (T2WI [five-point ordinal scale], DWI [five-point ordinal scale] and DCE-MRI [five-point ordinal scale]) will be evaluated through logistic regression with PCa as the binary outcome (Yes/No). The T2WI, DWI and DCE-MRI will be dichotomised by assigning 0 to scores 1–2, as well as 1 to scores 3–511, and presented as percentages and denominators in tables. The predictive performance of the dichotomised variables for the diagnosis of PCa will be analysed both individually and by considering all possible combinations among them. Additional variables as potential predictors in the logistic regression model will also include age, stage and comorbidity. Predictive ability will be estimated from the area under receiver operating characteristic (AUROC) curves drawn from the estimated probabilities given by the corresponding logistic regression models. Accuracy will be assessed by implementing the Hosmer–Lemeshow test for calibration. A score algorithm will be derived from the final logistic regression model.
1.5.2 Randomised Controlled Trial (Objective 2)
Analysis of the randomised comparison between MRI/US fusion-guided biopsy and standard TRUS-guided biopsy will be implemented according to the ICH E9 ‘Statistical Principles in Clinical Trials’. Analysis will be based on the intention-to-treat principle. The key outcome for the randomised study is to measure whether the MRI/US fusion-guided biopsy can improve the detection of cancer foci and to establish the reliability of the pre-biopsy MRI for the localisation of cancer foci within the prostate gland.
Secondary outcomes will include:
- PCa detected on fusion biopsy which are missed on TRUS biopsy.
- Safety outcomes of death, and side effects such as pain and bleeding with the severity and duration of symptoms recorded in each randomised group.
- Comparison of MRI negative standard care TRUS-guided biopsies with MRI positive TRUS histopathology to facilitate analysis of the diagnostic accuracy of MRI in men suspected of a target condition.
Binary outcomes such as cancer (Yes/No) and pain (Yes/No) will be analysed using logistic regression with the intervention arm as a binary variable in the model. All analyses will be stratified by site and minimisation variables and adjusted for prostatic volume and maximum lesion size. Outcomes such as Gleason Score (GS) and the number of lesions (depending on the range of values obtained) will be analysed as continuous linear regression or ordinal logistic regression. Subgroup analyses will be carried out as secondary analyses by adding treatment by subgroup variable interaction terms in the regression model. Analyses will be conducted by the study statisticians utilising SAS (9.4).
2.6 Data collection and management
The case report form (CRF) will be developed together with the trial management team, statistician and data manager to ensure that the data management system supports the research aims of the study. The data management system will be fully validated, including the provision of test data and supporting documentation. It is the CI’s responsibility to ensure the accuracy of all data entered and recorded in the CRF/Electronic Data Capture System (EDCS). Data will be stored on servers controlled by the HIC and housed at the University of Dundee. Back-up and disaster recovery will be provided by the HIC according to its standard operating procedures. The data in the CRF will be stored by the MULTIPROS study group for 5 years after the end of study. Future information on the EDCS is available upon request to the HIC.
2.7 Trial management, monitoring and auditing
2.7.1 Study management
Tayside Clinical Trial Unit, a UKCRC-registered trials unit will be responsible for overseeing management of the study. A dedicated trial specific manager will run the day-to-day work of the study and report to the CI. Specifically, the trial manager in consultation and close working with the CI, will ensure completeness and consistency of CRFs. The study management team will discuss any query and resolve it with the input from the CI. The CI may choose to delegate some of the tasks to a member. A details trial-specific Delegation Log will be made available at each recruiting site, with clear mention of the tasks each member of staff will be taking part in. The study management group consists of the Chief and co-investigators and representative of each participating sites. The TMG meets monthly to keep a track of progress with recruitment and resolve challenges as and when they arise.
2.7.2 Joint data monitoring committee and trial steering group charter
A Trial Steering Committee (TSC) with an integrated Data Monitoring Committee (DMC) will be put in place. The combined group will perform a patient safety review and provide overall strategic direction and supervision during the progress of the study. The DMC is integrated because the foreseen risks profile of the study is minimal. Membership will consist of a lay-member of patients group as Chair and a minimum of two other experts in area of trial management or treatment of prostate cancer. The CI will participate as invited by the TSC/DMC. The independent committee members will ensure research governance, review data and suggest alteration to study based on a risk-benefit analyses of the data. The later may include early termination of recruitment and other modifications as desired. The terms of reference will be agreed upon to clarify the membership, roles and responsibilities of the joint committee. All the processes and procedures will be documented in the MULTIPROS Joint Committee Charter.
2.7.3 Inspection of records
The CI, PIs and all the participating sites to the recruitment in the study will undertake a commitment to allow free study-specific monitoring, periodic audits and a Research Ethics Committee (REC) review. It is expected that the CI will sign an agreement to allow direct access to all the documentations and study-related records and material to study-sponsor or representative of the sponsor whenever needed.
2.7.4 End of study
The end of study for a participant is a date at which biopsy procedure was performed plus 30 days. The definition of the end of the study date for this trial is database lock. The Sponsor, CI and/or the management group reserve the right to close the study to recruitment for any reasons including safety of the participants, less than satisfactory infra-structure or lack of progress If the decision is taken to terminate the study prematurely, the decision of end of the study will be communicated to the Sponsor and REC within 90 days, or 15 days of the decision. The CI will be responsible for any further follow-up of the participants and their safety. The Sponsor and REC will be informed and a summary report of the study will be submitted to both within 1 year of the decision to end the study.
2.8 Harms
As the study does not employ an Investigational Medicinal Product, Adverse Events (AEs) and Serious Adverse Events (SAEs) will be recorded and reported as per Health Research Authority (HRA).
An SAE is defined as an untoward occurrence that:
- results in death;
- is life-threatening;
- requires hospitalisation or prolongation of existing hospitalisation;
- results in persistent or significant disability or incapacity;
- consists of a congenital anomaly or birth defect; or
- is otherwise considered medically significant by the investigator.
An SAE occurring to a research participant will be reported to the main REC and Sponsor where in the opinion of the CI the event is: Related – it results from administration of any of the research procedures and Unexpected – the type of event is not listed in the protocol as an expected occurrence.
Due to the clinical status of the study population we will record in the CRF but not report to REC or Sponsor, Serious Adverse Events (SAEs) in the following categories:
- Any death or hospitalisation due to new diagnosis or treatment of a cancer
- Any death or hospitalisation due to exacerbation of an existing medical condition
- SAEs due to expected side effects of biopsy as defined in the BAUS Transrectal Ultrasound-Guided Biopsies of the Prostate Gland Leaflet
AEs will only be recorded in relation to study procedures namely: MRI, biopsy procedure and post biopsy events. Participants will either be called or approached at the time of their routine clinic visit approximately 1-2 weeks following biopsy procedure, to record biopsy related AEs. It is anticipated that pain and bleeding will occur as a result of biopsy, but they will only be recorded as an AE if they continue for more than 4 days post biopsy.
2.9 Patient and public involvement
The research question was discussed in Tayside Urological Cancers Network (TUCAN) meeting with input from patients and public representation. The main attraction of proposal for patients and public was reducing the number of biopsies, improving detection of clinically significant cancers and avoiding having biopsies in men not needed. Patients helped in the preparation of lay-man summary during the grant application. They contributed to the design of information and consent forms. We have advertised study locally in the meetings with patients and public such as Dundee Prostate Cancer Group and Perth and Kinross prostate cancer and prostate diseases groups. The results will be summarised in a layman summary (briefing document) and widely publicised in local and national patients’ groups and prostate cancer charities. The advantages of intervention were discussed in patients and public engagement meetings.