Title: Adjustable Anchored Single-Incision Mini-Slings Versus Standard Tension-Free Mid-Urethral Slings in the Surgical Management Of Female Stress Urinary Incontinence; A Pragmatic Multicentre Non–Inferiority Randomised Controlled Trial: The SIMS Trial.
Funder: Chief Scientist Office, Scotland

Abstract: Design: A pragmatic multicentre non–inferiority randomised controlled trial comparing adjustable anchored single-incision mini-slings (SIMS) with standard tension free mid-urethral slings (SMUS) in women with Stress urinary incontinence (SUI). Setting: Twenty-five secondary and tertiary units across UK. Target Population: Women aged 18 years or over with SUI, for whom surgery has been indicated. All women will have failed or declined conservative treatment (supervised pelvic floor muscle training - PFMT). Women who have had previous continence surgery, anterior or apical Prolapse (>/= stage 2, pre-dominant overactive bladder (OAB) symptoms and/ or concomitant surgery will be excluded. Intervention: 1) Adjustable Anchored single-incision mini-slings (SIMS); and 2) tension-free standard mid-urethral slings (SMUS) including retropubic tension free vaginal tapes (RP-TVT) and transobturator tension free vaginal tapes (TO-TVT). Outcome Measures: This RCT will assess and compare adjustable anchored SIMS vs. tension-free SMUS with respect to: patient reported success rates; objective success rates; impact on urinary symptoms; women’s health related QOL; sexual function and costs to health services up to 3 years follow-up. We will use the same assessment tools and QOL instruments that were used in our pilot RCT which observed a 97% response rate. Primary outcome measures: 1.The primary outcome measure will be patient reported success rates measured by the validated patient global impression of improvement index (PGI-I) at 12-months. 2.The primary economic outcome will be incremental cost per QALY gained at 12-months. The above measures will be also be assessed at 2&3 years. Secondary outcome measures: 1.Peri-operative complications including: lower urinary tract injuries; haemorrhage (blood loss >/= 200mls); post-operative voiding dysfunction; other complications. 2.Post-operative pain using a pain Numerical Rating Scale (NRS): assessed day 1-14. 3.Objective success rates: assessed by 24 hour pad test at 12 month and yearly upto 3 years. 4.Other Lower urinary tract symptoms using the International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) at 3 & 12-months and yearly upto 3 years. 5.Health-related QOL profile (area under the curve) derived from EQ-5D, pain scores and ICIQ-FLUTSqol measurements at 4-weeks, 3 & 12-months and yearly upto 3 years 6.Recurrence of SUI, re-operation rates for SUI, further treatment received such as physiotherapy, medical treatment. 7.Secondary economic outcomes include; -NHS and patient primary and secondary care resource use and costs at 3-months; 12-months and yearly up to 3 years. -Incremental cost-effectiveness derived from responses to the ICIQ-FLUTSqol over the follow-up period at 12-months and yearly up to 3 years. -Incremental net benefit (NB) calculated from the responses to the discrete choice experiment (DCE) at 12-months. Sample size: The proposed trial design is non-inferiority so the sample size calculations reflect this. Published literature suggests that the P1, the percentage success rate at 12-months in the SMUS arm will be about 85%. Similar results were obtained from our pilot RCT. Power estimates were explored by simulating trials of fixed sample size (using equal allocation) with binary responses generated by P1=85% and P2=85%. Power was then estimated as the proportion of simulated trials where the lower bound of the 2-sided confidence interval satisfied P1-P2 > -10%. Simulations, run in Stata 11.2, show that a trial of 275/arm or 550 in total is required for the lower bound of the estimated 95% confidence interval to rule inferiority at the specified level with 90% power. Adjustment for potential 15% drop-out inflates the trial to 650 in total. For comparison, For comparison, a trial of this size would have above 80% power to test superiority on secondary outcomes of difference in means of size one quarter of a standard deviation. Project timetables & recruitment rate: Milestones are pre-funding: multicentre research ethics and central R&D approvals; months 1-6: study set-up authorisations; months 7-18: centre recruitment; months 7-44: recruit patients staggering centre start up (n=650); months 19-72: complete follow-up; months 73-78: close down and analysis.

Lay abstract: Urinary incontinence in women is a major issue for the NHS and for society, with the number affected and cost of treatment posing a significant burden of healthcare both now, and in the future with an ageing population. A large UK study has shown that a third of community dwelling women aged 40 and over had significant urinary symptoms, with 12% experiencing UI weekly. Female Stress Urinary Incontinence (SUI) is the involuntary loss of urine through exercise, laughing, sneezing or coughing. It is the most common form of incontinence in premenopausal women and can have a significant negative effect on women’s quality of life. It usually results from damage to the support of the urethra (the tube from the bladder to outside) during childbirth although symptoms may occur many years later. Primary non-surgical treatments seek to increase the support of the urethra with pelvic floor exercises but if these fail then surgery is the only alternative. In the most common surgical procedure, tension-free standard mid urethral slings (SMUS), a synthetic mesh (tape) is placed under the urethra to add support by creating a sub-urethral hammock. SMUS are done under general anaesthesia or deep sedation and the tape is held in place by friction to the surrounding muscles and ligaments but eventually becomes embedded-in by in-growth of body tissues; therefore women are instructed to limit their activities for an average of 4-weeks until the tape is reasonably integrated. Rare but serious complications can arise from the blind insertion of SMUS into the pelvis (such as bowel or major blood vessels injury) and occasionally thigh pain can occur for weeks and months after the operation. An alternative procedure known as adjustable anchored single-incision mini-sling (SIMS) is designed to have advantages over tension-free SMUS in that it avoids the blind insertion trajectory into the pelvic cavity or the thigh muscles while maintaining the concept of the hammock support to the urethra. The avoidance of the pelvic trajectory eliminates the risk of serious injuries such as bowel injury while avoidance of the thigh muscles trajectory led to substantive reduction in pain during and after insertion of the sling enabling this procedure to be done under pure local anaesthesia. In our preliminary study, we have shown the acceptability (70%) and feasibility (98%) of this relatively new procedure to be done under pure local anaesthesia i.e. without any sedation with high levels of women satisfaction at 6 & 12 months follow-up. One key advantage of the new procedure is that the tape is kept in place by a strong and secure anchoring mechanism to the pelvic side-walls and therefore women may not have to restrict their activities after surgery. This feature, together with avoidance of general anaesthesia and/or sedation, allows for rapid recovery after surgery; earlier return to normal activities, both of which would be potentially reflected in better improvement in women’s quality of life. Subsequently, we undertook a small comparative study comparing the new procedure (SIMS) to the standard surgery (SMUS) and this has shown SIMS to have fewer complications during the operation, shorter hospital stay, less pain after insertion (performed under pure local anaesthetic). Interestingly, women in our preliminary studies have resumed their professional activities significantly earlier than those who had the standard procedures, which if replicated on all patients will undoubtedly have economic benefits to both women themselves and the wider community. In summary the new procedure has potential advantage of being a truly ambulatory procedure with shorter hospital stay and earlier recovery with economic benefits to both the NHS & the wider community. However before this new procedure can be widely implemented in clinical practice it needs robust assessment to ensure (a) it is as effective as the current standard procedures and (b)to prove the above potential health & economic benefits. We propose to randomise 650 women from 25 UK centres to receive either a SIMS or SMUS procedure. Participation in the research will be voluntary and women will be provided with full information about the research. We do not believe that there are any specific risks of harm or adverse events involved in participating in this research. However, we shall provide information about supports that will be available to participants and what to do in the event of adverse events. We will follow their progress over the first 12 months, measuring potential benefits, risks and costs associated with each procedure and compare these outcomes and will be able then to present/ publish our first and primary report. However, as the durability of the successful outcomes of these procedures is quite important as it is not good enough to be successful at 12 month then the condition deteriorate/ recur and need another operation soon. Therefore we plan to follow-up women recruited in this RCT for 3 years to assess if this new technology lives up for its potentials compared to the standard procedures. This study RCT will therefore inform decision making for patients with SUI, their surgeons and the relevant policy makers. The study team is comprised of consultant surgeons working in collaboration with experienced health services researchers and patient/consumer representatives, all of whom have a track record of delivering large multi-centre randomised trials. If our preliminary results are confirmed in this definitive large trial we anticipate that SIMS will become the first choice surgical treatment for most women with stress urinary incontinence.

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