Title: Therapeutic Interventions for Stones of the Ureter (TISU): a multicentre randomised controlled trial of extracorporeal shockwave lithotripsy, as first treatment option, compared with direct progression to ureteroscopic retrieval, for ureteric stones.
Funder: Chief Scientist Office, Scotland

Abstract: DESIGN: A pragmatic multicentre non-inferiority randomised controlled trial of ESWL as first treatment option compared with direct progression to ureteroscopic retrieval for ureteric stones (incorporating an internal feasibility phase). HEALTH TECHNOLOGIES BEING ASSESSED: ESWL involves external to body generation of a shock-wave focused on the stone, causing it to fragment so it can pass spontaneously. It is routinely performed in an outpatient setting with pain relief or sedation as required. We will recruit centres with fixed-site lithotripters (allowing some standardisation of protocols on times to treatment and ESWL delivery). We will consider up to 2 sessions of ESWL as 1 intervention as per standard practice. Ureteroscopy is the use of small semi-rigid or flexible ureteroscopes, in conjunction with intracorporeal lithotripsy devices, such as the holmium laser to directly visualise and fragment ureteric stones. It is currently performed as a day-case procedure (but may require admission depending on complexity) and usually requires general anaesthetic. SETTING: Secondary care units with a high volume of ureteric stone admissions. Centre choice was informed by a national ureteric stone management audit (BAUS Section of Endourology 2007 co-led by our group). TARGET POPULATION: Symptomatic adults (>=18 years old) with no contraindications to ESWL or ureteroscopy, presenting with ureteric stones within any segment of the ureter (confirmed by CTKUB) who are judged clinically to require active intervention (e.g. who have either failed non-interventional treatment (conservative management) or are not suitable for such treatment). Randomisation will be stratified by stone type (>10mm or persistent small stone) and location (upper, mid or lower ureter). SAMPLE SIZE (Original): The proposed trial is a non-inferiority design. The sample size calculations reflect this. Published literature (Cochrane review and EAU/AUA Clinical Guidelines) suggests the proportion stone free without further intervention up to 6 months in the ureteroscopy arm will be about 0.75 (P1) and in the ESWL arm about 0.65 (P2). The margin of inferiority deemed acceptable is 0.20 (agreed at BAUS Endourology meeting), so that P2-P1> -0.20. The sample size was estimated using simulations, designed for this purpose, run in Stata. The power of a non-inferiority trial can be considered as the probability that the lower bound of the estimated confidence interval (CI) around the difference between trial proportions excludes the margin of non-inferiority. Simulating 1000s of trials of fixed sizes with the parameters P1 and P2 as above indicates that a trial of 450 per arm is required for the lower bound of the estimated 95% CI to exclude -20% with 90% power. Adjustment for potential 10% drop-out inflates the trial to 1000 in total. A trial of this size would have above 90% power to test superiority on secondary outcomes of effect size 1/4 of a standard deviation. SAMPLE SIZE (REVISED): Following poor recruitment and interim data analysis of 267 participants the sample size was amended from 1000 downwards to 750. The amendment has been ratified by the trial oversight committees and the sponsor and the funder. Recruitment projections showed us that the original sample size of 1000 was unachievable in a realistic timeframe despite measures implemented to improve recruitment. We agreed with the funder an extension of 18 months to reach a revised sample size of 750. Our original sample size of 1000 included a 15% uplift from 850 to perform the primary analysis under a suitably defined Per Protocol analysis. A Per Protocol analysis, in the special context of a non-inferiority design is often seen as the more conservative approach than the conventional intention to treat analysis. This Per Protocol analysis would have excluded any participants that crossed over from their randomly allocated treatment to the other, and would have excluded any participant whose stone cleared before their randomly allocated treatment was initiated. However, the view of the HTA Board, which has since been confirmed by the TISU iDMC, is that the intention to treat (ITT) approach should take primacy over this Per Protocol approach, to better reflect that the purpose of this pragmatic effectiveness trial is to compare the policy of initiating one or other of these treatment options, and not to focus on the actual comparative performance of the treatment options themselves. The Per Protocol approach will still be used as a supporting analysis. This is also a rare context in which there is no missing outcome data, since we are sure that we will have identified any further interventions to facilitate stone clearance in the 6 months post operatively - hence we can say with certainty for each individual randomised whether the original operation cleared the stone. Based on the 267 participants with mature outcome data as of the 16 February 2016, the iDMC observed that all the assumptions behind the power calculation remain plausible. Given that we are now committed to the ITT approach rather than the Per Protocol approach (and under, the original design of assuming the proportion stone free in ESWL arm would be 65%, and 75% in the ureteroscopy arm) the achievable sample size of 750 will give 85% power. If we recruit 750, under the assumption of 15% crossover and stone clearance, prior to initiation of the randomly allocated intervention, then the per protocol analysis of 638 subjects will still retain ~80% power under the same assumptions as above. MEASUREMENT OF COSTS AND OUTCOMES: Primary outcome measures: 1) Clearance of ureteric stones operationally defined as no further intervention required to facilitate stone passage up to 6 months. 2) Incremental cost per quality adjusted life years (QALYS) gained at 6 months based on the responses to the EQ5D. Secondary outcome measures: pre and 1 week post intervention, 2 and 6 months post randomisation: generic health profile (SF12) (2 & 6 months only); health status (EQ5D); severity of pain (NRS); analgesic use, time to stone clearance. At 6 months: complications; further interventions; NHS primary & secondary care use and costs; patient costs (out of pocket); incremental cost per intervention averted. Statistical analysis will be per protocol and intention-to-treat with estimates and 95% CIs derived from appropriate generalised linear models. Pre-specified subgroup analyses will explore potential treatment difference by size and location of stone. The main economic analysis will estimate the costs and effects (QALYs) of the treatments over the 6 month follow-up. Secondary and primary care resource use will be collected via CRFs and participant questionnaires. Out of pocket patient costs (time and travel) will be collected via 6 month questionnaire. Unit costs will be based on routine sources (e.g. BNF) or study specific estimates. QALYs will be based on the responses to the EQ5D. Sensitivity analysis will be used to explore the impact of statistical imprecision and other forms of uncertainty (e.g. basing QALYs on SF6D scores derived from responses to the SF12). PROJECT TIMETABLES: The study duration will be 48 months including an internal feasibility phase: Milestones å Months: 1-5 study initiation, NHS approvals; Months 6-18: Internal feasibility- staggered site start up recruit participants; Months 18-53: Continue to recruit patients - staggered start up (all by month 23); Months 11-60: patient follow up completed; Months 61-66: close down, analysis, report writing.

Lay abstract: 1.8 million adults in the UK are affected by urinary stones. In some patients the stone travels and becomes lodged in the tube (ureter) between the kidney and bladder. This leads to excruciating pain in the abdomen and back (ureteric colic) that requires strong painkillers and often leads to emergency hospital admission. In most people the stones will pass in the urine within a few days but in 25% the stones need to be physically removed using the standard treatment options of either ureteroscopy or extracorporeal shock wave lithotripsy (ESWL). Ureteroscopy involves putting a telescope into the ureter and using a laser to break up the stone. ESWL breaks the stone into smaller pieces using a machine that passes shock-waves through the body. Both treatments are effective at getting rid of stones but have advantages and disadvantages. We are uncertain which of these standard treatments is best at getting rid of the stone in the most efficient way for the patients and the NHS. Our study involves giving either ESWL or ureteroscopy to 1000 people with stones in the ureter that need removal, who agree to take part. They will be randomly allocated to have either ESWL or ureteroscopy to remove their stones. The study will include a network of UK hospitals over 60 months with each participant being studied for 6 months. We will measure whether any additional treatments are needed and what they are, the impact of the treatments on the health of the participants and pain experienced, any complications arising and which treatment represents best value for money. This information will be collected by asking the participants to complete 5 questionnaires over the 6 months and by staff at the study hospital completing case report forms. We will start the study in at least three hospitals to assess whether we can recruit the necessary number of participants and deliver the intervention as expected. Our research team is made up of specialists (urologists) who perform the procedures, a lay expert and experts in the design, performance and analysis of clinical trials. The study will be managed by a Clinical Trials Unit which is very experienced at running large multicentre randomised controlled trials within the NHS. We also have the support of the national organisation of doctors who treat ureteric stones. We will convene a Trial Steering Committee and Data Monitoring Committee which will meet annually to oversee the trial progress. The study will last 66 months. This includes 5 months to set up the study; 47 months to set up the centres, recruit participants and deliver the interventions, a further 8 months to complete the follow up on all participants and 6 months to analyse, write up and close down the study.

Research activity codes: 6.3 MEDICAL DEVICES;6.4 SURGERY
Health categories: RENAL AND UROGENITAL