Title: A randomised controlled trial to determine the clinical and cost effectiveness of thulium laser transurethral vaporesection of the prostate(ThuVARP)versus transurethral resection of the prostate(TURP)in the National Health Service(NHS).
Funder: Department of Health (England)

Abstract: Design: In this pragmatic study design centres will use their usual practices for example discretionary pressure-flow urodynamics for patient selection or use of monopolar or bipolar TURP. Follow-up will be at 3 & 12 months (primary endpoint) from the time of surgery (also the time of randomisation) for the patient reported outcome (PRO) of the International Prostate Symptom Score(IPSS) and the maximum urine flow rate (Qmax). Patients will be asked to complete PROs at 6 weeks after surgery (by post) and at 3 & 12 months at clinic visits. To increase compliance with follow-up patients will be reminded by phone to complete their PROs and to attend their appointments.Setting: The study will be conducted in 3 university teaching hospitals (Bristol Aberdeen Newcastle) and 3 district general hospitals (Swindon Cheltenham Bath). Strategy for reviewing literature: European Urology the leading urology journal has recently published a systematic review of laser technology in Urology which recommended ThuVARP as an acceptable alternative to TURP for the treatment of symptomatic BPO. These recommendations were based on 6 studies of ThuVARP: two with a control group but only one randomised controlled trial (RCT). The RCT was conducted in China and randomised 100 consecutive men to ThuVARP or TURP at a single centre. A further case series from a UK centre has been published since the review showing good intermediate-term results. A paper published December 2012 showed that ThuVARP is a safe procedure compared to TURP.Target population: Men who are fit to have prostate surgery for either bothersome lower urinary tract symptoms (LUTS) or urinary retention secondary to BPO. Measurement of costs and outcomes: The cost-effectiveness analysis will take a societal perspective with NHS costs reported separately. Only resources used in relation to the treatment of LUTS or urinary retention secondary to BPO will be measured from randomisation at the time of surgery to 12 months follow-up. Details of initial hospital stay resource use e.g. operation duration operating staff consumables the time spent in recovery length of stay on different wards overall length of stay and treatment for complications will be collected on study designed case report forms by the research nurse at the time of the inpatient/day-case stay for the initial surgery. At 12 months follow-up any subsequent in-patient stays out-patient visits and procedures occurring in the initial treating hospitals will be abstracted from the patients’ medical records. On discharge from hospital and at 3 months follow-up the patients will be given a study designed Resource Use Log (RUL) to be used as an aide memoire in which to record NHS community based and other NHS hospital health care use medications social service resource use in addition to travel time off work/usual activities and any other expenses resulting from their treatment. These logs will reflect the design of the 3 & 12 month resource use questionnaires. At 3 & 12 months follow-up self-completed resource use questionnaire will be given to the patients to fill out using the information from the RUL. The EQ-5D-5L will be used to calculate quality adjusted life years (QALYs). The new 5-level EQ-5D will be used in preference to the 3-level one owing to its improved discriminatory power. The IPSS and Qmax are internationally accepted and the most frequently used primary outcomes in BPO studies thereby making results from this study comparable to others. There are no core outcomes measures for BPO listed in the COMET Initiative website.Sample size: This study is powered to establish equivalence in clinical improvement. The Chinese trial observed differences of 0.4 ml/s (95% CI: -2.0 to 2.8) in Qmax and 0.4 units(-0.7 to 1.5) in IPSS between ThuVARP and TURP. Variability(standard deviation;SD) in data at 12 months was approximately 6.0 ml/s (Qmax) and 3.0 units (IPSS) but previous trials of TURP report greater variability around 9 ml/s (Qmax)and 5 units IPSS. After considerable discussions between clinicians we have specified differences of 4 ml/s and 2.5 units as demonstrating equivalence (null hypotheses). Equivalence studies often use an alternative hypothesis of a difference of zero between treatments. However the Chinese trial observed differences of around 0.5 ml/s and 0.5 units for Qmax and IPSS. Incorporating these as alternative hypotheses ensures adequate power to demonstrate equivalence if treatments are indeed similar but not identical. Assuming SDs of 9 ml/s for Qmax and 5 units for IPSS the target sample size for patients needed to complete the 12 month follow-up is 163 patients in each group. Using NQuery Advisor this will provide 85% power to demonstrate equivalence for IPSS and just over 90% power for Qmax at a two-sided alpha of 5%. Assuming 20% loss to follow-up following randomisation it will be necessary to recruit 410 men in total. This loss to follow-up is a conservative estimate from our experience from previous trials. However we will aim to reduce loss to follow-up through letter text and telephone reminders to patients.Project timetables including recruitment rate: Each surgeon will be initially declared competent by the mentor after completing 5 supervised ThuVARP procedures during the study set-up period. This will be followed by a maximum of 10 further procedures following which the mentor will return for the last procedure and confirm the surgeon is competent according to agreed trial criteria. 15 is the number required to assure competence based on the experience of the chief investigator and others who perform the procedure and the fact that the resection technique is similar to TURP and therefore the skill is generalisable. If not competent then the surgeon will perform more procedures until he/she is signed-off as competent. Each centre performs between 150-400 TURPs per year. The accrual target of 410 can be achieved within a 15 month recruitment period assuming 70% are eligible and 50% randomisation (62% in the ProtecT trial between three treatments). Each centre will randomise on average 4 to 5 men per month although our prior experience shows that recruitment generally increases over time. The study duration of 36 months comprises a set-up/site initiation period of 5 months 15 months recruitment 12 months follow-up and 4 months data analysis and dissemination.


Research activity codes: 6.4 SURGERY
Health categories: RENAL AND UROGENITAL