Title: Randomised double-blind controlled efficacy and mechanism study of sub-sensory sacral neuromodulation in adults with faecal incontinence
Funder: Department of Health and Social Care

Abstract: HYPOTHESIS AND AIMS The study will determine the efficacy of chronic low voltage electrical sub-sensory sacral nerve-root stimulation: SNM (using a commercially-available implantable device) to reduce frequency of FI episodes. It will also aim to identify the effect of SNM on anorectal and anocortical functions. DESIGN Double-blind randomised crossover: Following implantation and a 2 week stabilisation period, participants will be randomly allocated to two trial arms with two intervention periods of 16 weeks duration in random sequence (ON or OFF). Efficacy outcomes will be derived from assessments in the final 4 weeks of each crossover period thus allowing for almost 3 months wash out in both arms. A subgroup of patients will participate in the mechanistic studies. POPULATION Adults, aged between 18-75 meeting Rome III and ICI definitions of FI failing conservative treatment to NICE eligibility standard will be recruited from surgical waiting lists of up to 20 participating centres using a standard list of inclusions and exclusions. INTERVENTIONS SNM: (Medtronic Interstim ®). Implantation under general or local anaesthetic + sedation by expert surgeons using recently standardised procedural steps. ON = chronic subsensory stimulation using standard parameters of 14Hz, 210usec at 75% habituated sensory threshold; OFF = sham stimulation with stimulator turned off. OUTCOMES PRIMARY EFFICACY: Frequency of FI episodes per unit time will be assessed using 4-week paper bowel diaries. The outcome of primary interest is the expected number of FI events per 4 week assessment period for SNM as compared with the expected number of events with sham simulation. The study is powered to detect a ratio of 0.7. Data will be analysed on intention-to-treat principles and blind to intervention status. SECONDARY EFFICACY: (1) E-event recorder including episodes of faecal material, leakage of flatus, urgency without incontinence, social and physical activity; (2) Other bowel diary measures: urgency episodes, number of controlled bowel movements; usage of incontinence pads and antidiarrhoeal medication; (3) Summative questionnaire assessments: St Mark’s continence score; OAB-Q SF score, FI QoL score; International Consultation on Incontinence Bowel Short Form (SF-ICIQ-B) questionnaire; (4) Viscerosensory bowel diary recording quality, site and intensity of defaecatory urge; (5) Generic QOL: EQ-5D-5L; (6) Likert scale of patient’s global impression of treatment success (scale 0-10); (7) Electrode settings (inc. motor, first and habituated sensory thresholds), programming & if applicable, re-programming data; (8) Adverse events and morbidity. MECHANISM: anorectal reflex motor events (by prolonged [2-hour total], fasting & fed high-resolution anorectal manometry); anorectal afferent function (electrical and volumetric); anocortical function (by magnetoencephalography). SAMPLE SIZE 80 participants are required (at 90% power and 5% sig. level). Allowing for 10% drop-out, a total of 90 participants will be randomized. A sub-sample of 25 patients is sufficient to detect changes in main mechanistic outcomes based on pilot data. RECRUITMENT FEASIBILITY AND STUDY DURATION Based on recruitment of 18 months in 20 centres with conservative implantation estimates of 30 per annum per centre, a 10% recruitment rate is required (90/[30*20*1.5]) [based on 20 centres]. In trial participation = 58 weeks; total study duration = 32 months. ECONOMIC BENEFIT Efficacy data (particularly effect size) will promote (or refute) therapeutic confidence and inform international guidance. Mechanism data will aid patient selection and procedural optimisation (and basic understanding of FI pathophysiology).

Lay abstract: A relatively new treatment called sacral neuromodulation (SNM) is now commonly offered to adults suffering with faecal incontinence. Suitable patients include those with faecal incontinence caused by childbirth, surgery, and advancing age. A battery powered unit is implanted into the lower back in the region of the sacrum (tailbone). This is connected to a specially developed lead with electrodes which rest on the nerves in the lower spine (most commonly the third sacral nerve). This stimulator then continuously sends electrical impulses to the nerves and muscles that control the lower bowel (rectum and anus). The result may improve continence. Previous studies have reported a great benefit of SNM in some patients. Unfortunately, other patients can have little or no response. We are still unsure about how SNM restores bowel control. And we still do not know with certainty how effective SNM really is. SNM costs on average £10,000 per patient just for the equipment and while a very safe therapy in comparison with other surgery still has some risks e.g. infection and unwanted side-effects. It is therefore vital that these questions are answered. This research aims to establish how SNM works and how well SNM works. Patients who meet the current national criteria for SNM will be invited to participate in our trial. They will undergo detailed evaluation of their symptoms. Some will also undergo specialist tests before and after treatment. These will study their anal and rectal function as well as their corresponding brain activity (using a special test called magnetoencephalography). In contrast to a traditional clinical trial, the design of this trial will allow all patients to receive the treatment. This is possible by using a crossover design i.e. one where after implantation of the stimulator all patients receive a period of real therapy (device on but at an unperceived level of stimulation) compared to a period of sham (placebo) therapy (device off). The effects of SNM can then be compared while both the patients and the research team are unaware whether the stimulator is on or off. This is called ‘double-blinding’ and is the gold standard for determining what the true effects of the treatment are. The study will be led by Barts Health NHS Trust and Queen Mary University of London. It will be performed in several NHS and European specialist centres and at the Aston Brain Centre (Birmingham). The trial will include a total of 90 patients. Each patient will participate for just over 12 months, but their SNM treatment will continue thereafter.

Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL